JP2008536851A - How to increase testosterone and related steroid levels in women - Google Patents

Abstract

The present invention relates to methods, kits, combinations and compositions for the treatment, prevention or reduction of the risk of developing testosterone deficiency disorder or symptoms associated with or associated with testosterone deficiency disorder in a subject in need thereof. The invention also relates to a method of administering a testosterone synthetic steroid to a subject in need thereof.
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Description

  This application claims priority to US Provisional Application No. 60 / 670,753 filed Apr. 13, 2005, the entire contents of which are hereby incorporated by reference.

  The present invention relates to methods, kits, combinations and compositions for delivering an effective amount of testosterone transdermally to a subject in need thereof.

  The testosterone transdermal formulation provided a delivery system that normalized serum testosterone levels in hypogonadal men and prevented clinical symptoms and long-term effects in androgen-deficient men. Available transdermal formulations of testosterone include, for example, TESTODERM (registered trademark), TESTODERM (registered trademark) TTS, and ANDRODERM (registered trademark). Testosterone is available as an injection, eg DEPO-TESTOSTERONE® (Testosterone Cypionate) and DELATESTRYL BTG® (Testosterone Enanthate), or available as a gel, for example the assignee of this application Other formulations are also available, including ANDROGEL®, commercially available from Unimed Pharmaceuticals, Inc., Deerfield, Illinois.

  In men, transdermal patches are applied to scrotal skin or other parts of the body. In recent years, 1% testosterone gel has been approved for men and provides dosage flexibility with minimal skin irritation. This gel is marketed under the name ANDROGEL®. However, all testosterone transdermal products available today are particularly contraindicated for use in US women. Furthermore, none of the androgen treatment modalities available today for women, such as oral methyltestosterone, intramuscular testosterone ester injections or subcutaneous testosterone implants, can achieve consistently reproducible testosterone serum levels daily.

A. Testosterone Physiology in Women Excretion of androgen steroids in the urine of adult women was shown before 50 years. Since that time, physiologists and clinicians have investigated the source and biological function of testosterone and other endogenous male hormones in human women. For example, see Non-Patent Document 1. Androgens are now known to be secreted by the ovaries and adrenal glands in women. Each source contributes about 300% of testosterone produced daily by healthy “in cycle” women (eg, non-patent document 2) about 50% (directly and through precursors) (eg, non- (See Patent Document 3). The adverse effects of excessive androgen production that occur in polycystic ovary syndrome and certain androgen-producing tumors have been described in detail (see, for example, NPL 4), but there is much less understanding of the normal physiological effects of androgens in women . As inferred from animal studies, male physiology and symptoms of androgen production deficient women, androgen's major physiological effects in normal women include, but are not limited to, anabolic effects on muscle, skin, hair and bone There are stimulatory effects on erythropoiesis, regulatory effects on immune function, and psychological effects on emotion, happiness and sexual function.

  In addition, endogenous androgens are important for pubic hair development and are thought to modulate the effects of estrogens and progestins on various reproductive target tissues. Androgens are also thought to play an important role in regulating the lacrimal gland secretion function.

  50% of circulating testosterone comes from direct ovarian secretion in follicular membrane cells under the control of luteinizing hormone. The other half comes from the peripheral conversion of the adrenal androgen precursors dehydroepiandrosterone, androstenedione and dehydroepiandrosterone sulfate. Testosterone is also converted to dihydrotestosterone or estradiol. Therefore, testosterone serves as a hormone and prohormone.

  Testosterone circulates in the blood with 98% binding to protein. In women, about 65% of the binding is with high affinity sex hormone binding globulins. The remaining 33% binds weakly to albumin. Therefore, some of the testosterone measurements are available in clinical laboratories. As used herein, the term “free” testosterone refers to the fraction of testosterone in the blood that is not bound to protein. As used herein, the term “total testosterone” or “testosterone” means free testosterone plus testosterone bound to a protein. As used herein, the term “biologically available testosterone” refers to non-sex hormone-binding globulin-binding testosterone, including those that are weakly bound to albumin as well as those defined as “free”. The order of affinity of the steroids that binds most strongly to sex hormone binding globulin is: dihydrotestosterone> testosterone> androstenedione> estrogens. Sex hormone-binding globulin binds weakly to dihydrotestosterone, but dihydrotestosterone sulfate does not. Table 1 shows approximate hormone levels in normal premenopausal women.

  However, since it has historically been impossible to develop assays that can measure such low hormone levels, there is no general consensus as to what constitutes “testosterone deficiency” in women. This is especially true in measuring the level of free or bioavailable testosterone. Thus, today's available laboratory assessments, including measurement of total, free and bioavailable serum testosterone levels, have not been widely used to identify women with hypoandrogenism.

B. Androgen administration in women In comparison with other hormone deficiency states, female testosterone deficiency was largely ignored and not defined as a clinical entity. Still, there is a clear patient population with a clear deficiency in androgen production and related symptoms, including young women who have been ovariectomized / hysterectomized, estrogen replacement menopausal women, oral contraceptives Women with adrenal function, women with adrenal dysfunction, women with adrenal suppression induced by corticosteroids, and women immunopositive for human immunodeficiency virus.

  Despite the clear benefits of administering testosterone to normal women and testosterone deficient women, almost all testosterone delivery formulations for humans require gonad function that requires significantly higher amounts of testosterone than testosterone deficient women Designed for hypotensive men. As a result, these formulations and devices are generally unsuitable for women who require low doses of testosterone. For example, intramuscular injection of testosterone ester is a popular form of male androgen supplementation but is unsatisfactory for women because of the very high levels of testosterone in the first few days after injection. In addition, many women report an increase in acne and occasional clitoral hypertrophy with this type of testosterone administration. Patients receiving injection therapy often complain that the delivery mechanism is painful and causes a local skin reaction.

  Since increasing testosterone levels have been shown to alter sexual performance and libido, researchers have investigated ways to deliver testosterone to men. These methods include intramuscular injection (43%), oral replacement (24%), pellet implants (23%) and transdermal patches (10%). A summary of these methods is shown in Table 2.

  However, none of the current testosterone replacement products available to women are approved in the United States for chronic treatment of female testosterone deficiency conditions as described herein. Also, the methyl testosterone products available today can be administered orally, but are no longer recommended as testosterone replacement for men with hypogonadism. For example, see Non-Patent Document 5. Long-acting testosterone-ester injections, such as enanthate or cypionate, are formulated for high dose (eg, 200-300 mg) administration to men and lower doses (eg, 50-100 mg) for women. Even when administered in the same manner, the physiological hormone concentration is exceeded (see, for example, Non-Patent Document 6). Testosterone implants have been used experimentally in the past, but similarly exceed physiological hormone levels in women. For example, see Non-Patent Document 7. The superphysiological androgen levels associated with these products have caused side effects that cause masculinization in some patients. For example, see Non-Patent Document 7. See also Non-Patent Document 6, for example. See also Non-Patent Document 8, for example.

  However, in view of the above, ESTRATEST®, a combination of an oral tablet formulation of methyltestosterone and an estrogen ester, is the most commonly used androgenic product for the treatment of women in the United States. However, currently its only approved application is for the treatment of moderate to severe vasomotor symptoms associated with menopause in patients who are not improved with estrogen alone. Higher pharmacological doses of methyltestosterone than those recommended in hypogonadal men have also been used to treat female breast cancer. However, oral administration results in inadequate testosterone levels and unpredictable absorption patterns in patients (see, for example, Non-Patent Document 9). Furthermore, since the liver metabolizes the formulation, there is a risk of liver toxicity, not to mention first pass metabolism.

  Testosterone pellet implants (50 mg or 100 mg testosterone) inserted into the abdominal wall under local anesthesia have been used with estrogen pellet implants for many years. Testosterone levels peak after approximately one month after transplantation and then return to baseline by the fifth or sixth month. Testosterone levels are high and are characterized by considerable rise and fall over several months, as well as individual significant fluctuations during this period. Furthermore, implants require surgical procedures that many men and women simply do not want to withstand. For example, in hypogonadal men, implant therapy involves the risk of protrusion (8.5%), bleeding (2.3%), or infection (0.6%).

  In view of the problems associated with injection, oral administration and implant-based testosterone delivery methods, researchers have recently experimented with more controlled sustained release formulations that can deliver stable physiological testosterone levels to women Started. Over the past decade, transdermal delivery of estradiol has been recognized as a safe, physiological and patient-friendly method for female estrogen replacement therapy. A second generation estradiol patch using sticky matrix technology has recently become available in the US and Europe. Matrix technology now exists for the transdermal administration of physiological amounts of testosterone alone for the treatment of female androgen deficiency conditions. Since the patient population defined above lacks about 50% of testosterone production, the transdermal system is designed to deliver about half the normal daily testosterone production, ie about 150 μg per day. Yes. Matrix technology-based transdermal testosterone administration has been used successfully in women to treat acquired immune deficiency syndrome exhaustion and female sexual dysfunction after ovariectomy.

Two testosterone patches for women were tested in clinical trials. Buckler and his collaborators investigated a testosterone patch (Ethical Pharmaceuticals, UK) that delivered 840, 1100, 3000 μg of testosterone daily administered to the anterior abdominal wall twice a week, but disclosed the composition of the patch. There was not (nonpatent literature 9). Another patch TMTDS patch (Watson Laboratories, Salt Lake City, UT) is translucent with a surface area of 18 cm ² using sorbitan monooleate and a hypoallergenic acrylic adhesive as a penetration enhancer in an alcohol-free matrix. This is a patch. The average testosterone content of each patch is 4.1 mg. Each patch is designed to deliver testosterone at a nominal rate of 150 g testosterone per day over a 3-4 day dosing period. Therefore, a TMTDS patch is administered twice a week (for example, refer nonpatent literature 10).

  Although clinical trials have reported that testosterone-containing patches can increase testosterone levels in women through a controlled release mechanism, these patches do not provide dosage flexibility. In addition, their visibility can be aesthetically pleasing to some women and can be stripped off, especially during severe physical exercise.

Geist S.H., "Androgen therapy in the human female", J. Clin. Endocrinol. 1941; 1: p. 154-161 Abraham G.E., “Ovarian and adrenal contribution to peripheral androgens during the menstrual cycle”, J. Clin. Endocrinol. Metab., 1974; 39: p. 340-346 Southren AL et al., “Further study of factors affecting the metabolic clearance rate of testosterone in man”, J. Clin. Endocrinol. Metab., 1968; 28: p. 1105-1112 Lobo RA, Chapter 20: “Androgen excess in Infertility, Contraception and Reproductive Endocrinology”, Third Edition, DR Mishell, V. Davajan and R. Lobo, Blackwell Scientific Publications, Boston, 1991, p. 422-446 E. Nieschlag and HM. Behre, “Testosterone: Action, Deficiency, Substitution”, Springer-Verlag, Heidelberg, 1990, p. 136 Sherwin BB and Gelfand MM, “Differential symptom response to parenteral estrogen and / or androgen administration in the surgical menopause”, Am. J Obstet. Gynecol., 1985; 151: p. 153-160 Burger HG et al., “The management of persistent menopausal symptoms with oestradiol-testosterone implants: clinical, lipid and hormonal results”, Maturitas, 1984; 6 : P. 351-358 Urman B. et al., “Elevated serum testosterone, hirsutism and virilism associated with combined androgen-estrogen hormone replacement therapy”, Obstet. Gynecol., 1991; 7: p. 595-598 H. M. Buckler et al., “Which Androgen Replacement Therapy for Women?” Journal of Clinical Endocrinology and Metabolism., 1998; 83; p. 3920-3924 Marjan Navanbakht et al., “Pharmacokinetics of a Novel Testosterone Matrix Transdermal System in Healthy, Premenopausal Women and Women Infected”. with the Human Immunodeficiency Virus), Journal of Clinical Endocrinology and Metabolism., 2000; 85; p. 2395-2401

  Thus, for these and other reasons, effective transdermal administration, which can be administered directly to the subject, particularly female skin, for example in the form of a gel, ointment or cream, for example to treat a testosterone deficiency disorder Providing a testosterone formulation would be a difficult but highly desirable advance in the art.

  A pharmaceutical composition comprising a testosterone synthetic steroid has been discovered that can effectively transdermally deliver a therapeutically effective amount of the drug to a female subject. In one embodiment of the present invention, a composition comprising a testosterone dosage of about 0.4 mg to about 0.9 mg provides improved bioavailability, chemical stability, physical stability, safety, and other It has been discovered that it has improved pharmacokinetic, pharmacodynamic, chemical and / or physical properties. The present invention includes these pharmaceutical compositions, dosage forms and kits based thereon, and methods for their preparation and use.

  While the invention may be embodied in many different forms, it should be understood that this disclosure is to be considered merely as illustrative of the principles of the invention and is not intended to limit the invention to the illustrated embodiments. Thus, some specific embodiments are discussed herein. The methods, kits, combinations and compositions of the present invention provide enhanced therapeutic options compared to those available today for treating testosterone deficiency disorders in a subject, eg, a woman.

  Where the present invention is exemplified herein specifically with respect to testosterone, any other steroids of the testosterone synthesis system may optionally be substituted for testosterone in the methods, kits, combinations and compositions described herein. It is understood that all or part can be replaced. Where the present invention is exemplified herein with particular reference to methyltestosterone, any other inhibitor of sex hormone binding globulin synthesis, optionally in the methods, kits, combinations and compositions described herein, It is understood that all or part of the methyl testosterone can be substituted. Where the present invention is exemplified herein with particular reference to estradiol, any other estrogen hormones may optionally be substituted in whole or in place of estradiol in the methods, kits, combinations and compositions described herein. It is understood that parts can be substituted.

  The present invention is directed to methods, kits, combinations and compositions for the treatment, prevention, and reduction of the risk of developing testosterone deficiency disorder or symptoms associated with or associated with testosterone deficiency disorder in a subject in need thereof. To do. In one embodiment of the invention, the subject is a woman. The method includes transdermally administering to a subject a testosterone deficiency effective amount of a testosterone synthetic steroid, such as testosterone. The present invention includes methods for reversing, stopping or slowing the progression of testosterone deficiency once clinically evident, or for treating symptoms associated with or related to testosterone deficiency . The subject may have already developed a testosterone deficiency disorder at the time of administration or may be at risk of developing a testosterone deficiency disorder. A method of administering a testosterone synthetic steroid, such as testosterone, to a mammal in need thereof is also included in the present invention. This method involves a transdermally deliverable composition comprising a pharmaceutically acceptable steroid of the testosterone synthesis system, such as testosterone, one or more lower alcohols such as ethanol or isopropanol, a penetration enhancer, a thickener and water. Administration of an effective amount of testosterone deficiency disorder to the subject. Pharmaceutical compositions comprising an effective amount of testosterone deficiency disorder for testosterone are also included in the methods, kits, combinations and compositions of the present invention. In one embodiment, the testosterone composition is formulated as a hydroalcoholic gel. In other embodiments, the gel comprises testosterone, one or more lower alcohols such as ethanol or isopropanol, penetration enhancers, thickeners, and water. The invention also includes a kit comprising testosterone that is transdermally deliverable. The kit can also include a set of instructions for the patient.

  In other embodiments, these methods, kits, combinations and compositions are used in combination with other steroids or agents effective in treating, preventing or reducing the risk of developing testosterone deficiency disorders in a subject. In one embodiment, the present invention using testosterone is combined with a pharmacologically effective amount of an estrogenic hormone, such as estradiol in the same dosage form or another dosage form. In other embodiments, these methods, kits, combinations and compositions are used with other steroids or agents that increase testosterone levels in mammals, such as testosterone. In addition, the invention optionally includes salts, esters, amides, enantiomers, isomers, tautomers, prodrugs or derivatives of the compounds of the invention, as well as mitigating agents, stabilizers, antibacterial agents, fragrances and propellants. Contains agents. The methods, kits, combinations and compositions of the present invention provide enhanced therapeutic options compared to those available today for treating testosterone deficiency disorders in a subject, eg, a woman.

  Besides serving human treatment, the present invention is also useful for other subjects such as veterinary animals, reptiles, birds, exotic animals and farm animals including mammals, rodents, and others. Mammals include primates such as monkeys or lemurs, horses, dogs, pigs or cats. Rodents include rats, mice, squirrels or guinea pigs.

  The use of the term “adult female premenopausal subject” refers to a fully grown mature female mammal, such as a human, capable of menstruation, including periodic endometrial shedding during the menstrual cycle and drainage of blood fluid from the uterus. Point to. In healthy subjects, this periodic shedding and excretion occurs at regular intervals, for example, approximately every 4 weeks in humans, and under normal circumstances, after ovulation and pre-endometrial changes. (See, for example, Stedman's Medial Dictionary, 25th edition).

  The use of the term “adult female postmenopausal subject” refers to a fully grown mature female mammal, such as a human, who has undergone menopause, ie cannot menstruate because of a permanent cessation of the menstrual cycle. (See, for example, Stedman's Medial Dictionary, 25th edition).

  The use of the term “subnormal free testosterone plasma concentration” refers to premenopausal or postmenopausal adult female subjects having free testosterone plasma concentrations of less than about 0.2 ng per dl serum to about 0.5 ng per dl serum. Point to.

  As used herein, the term “treat” or “treatment” refers to any treatment of a mammal condition, disorder or disease associated with androgen deficiency or testosterone deficiency, including, but not limited to, a disease state Preventing the occurrence of a disease state, disorder or disease in a mammal that may have a predisposition to the disorder or disease but has not yet been diagnosed with the disease state, disorder or disease, or suppressing the disease state, disorder or disease E.g., preventing the onset of a disease state, disorder or disease, reducing the disease state, disorder or disease, e.g., providing recovery from a disease state, disorder or disease, or removing a disease state caused by the disease or disorder For example, stopping the symptoms of the disease or disorder.

  The term “prevent” or “prevention” in relation to a testosterone deficiency condition, disorder or disease is the absence of the development of a testosterone deficiency condition, disorder or disease if they are not occurring, or the development of a testosterone deficiency condition, disorder or disease If already exists, it means that there are no further testosterone deficiency conditions, disorders and diseases.

  The term “testosterone deficiency disorder” refers to a condition, disorder, or disease that occurs in a mammal due to a lack of endogenous testosterone production or its utilization. In women, such conditions, disorders or diseases include, but are not limited to hypogonadism, sexual dysfunction (eg, libido, sexual arousal disorders, orgasmic disorders (eg, sexual stimulation) Sexual genital lubrication or hyperemia on a continuous or daily basis) and sexual pain disorders), decreased libido, hypercholesterolemia, abnormal electrocardiogram, vasomotor symptoms, diabetic retina Symptom, hyperglycemia, hyperinsulinemia, hypoinsulinemia, increased body fat percentage, hypertension, obesity, osteoporosis, osteopenia, vaginal dryness, thinning of the vaginal wall, climacteric symptoms and hot flashes, cognitive impairment, cardiovascular Disease, central nervous system disorder, Alzheimer's disease, dementia, cataract, cervical cancer, uterine cancer, breast cancer, depression (eg postpartum depression), in vitro fertilization (eg inappropriate in utero Implantation), there is a premature ovarian failure and premature menopause.

  As used herein, the term “therapeutically effective amount” means an amount effective to sufficiently deliver the therapeutic agent of the present invention to achieve a desired therapeutic effect in the treatment of a condition. The amount comprising the therapeutically effective amount is the condition being treated, e.g. hypogonadism, sexual dysfunction, decreased libido, hypercholesterolemia, abnormal electrocardiogram, vasomotor symptoms, diabetic retinopathy, hyperglycemia , Hyperinsulinemia, hypoinsulinemia, increased body fat percentage, hypertension, obesity, osteoporosis, osteopenia, vaginal dryness, thinning of the vaginal wall, climacteric symptoms and hot flashes, cognitive impairment, cardiovascular disease, central nervous system System disorders, Alzheimer's disease, dementia, dementia, cataract, cervical cancer, uterine cancer, breast cancer, depression (eg postpartum depression), in vitro fertilization (eg improper embryo implantation in the uterus), premature Depending on the choice of ovarian failure and premature menopause, any drug co-administered with the therapeutic agent, the desired duration of treatment, the surface area and location of the skin to which the composition is administered, and other components of the adjuvant and compositionThus, it is not practical to enumerate specific exemplary amounts, and such can be readily determined by one of ordinary skill in the art in view of these and other suitable factors, but some Such non-limiting examples are provided herein for illustrative purposes.

  As used herein, the terms “androgen deficiency” or “testosterone deficiency” are used interchangeably and indicate a low free testosterone serum level in a subject compared to the median serum level of healthy women of the same age. Point to. In women with a normal cycle, about 300 μg of testosterone is produced per day. Their total serum testosterone levels generally range from about 20 ng / dL to about 80 ng / dL, with an average of about 40 ng / dL. For example, in healthy young women, the average free testosterone level is generally about 3.6 pg / mL. However, several factors can affect total and free testosterone serum levels. For example, women who ovulate regularly have a small but significant increase in plasma testosterone levels during the middle third of the menstrual cycle. However, there is no significant difference in mean testosterone levels (1.2 nmol / L or 33 ng / dL) and mean free testosterone levels (12.8 pmol / L or 3.6 pg / mL) in the luteal and follicular phases. Furthermore, since testosterone production declines continuously after age 30, serum testosterone levels in 60 year old women are only 50% of those in young 30 year old women. The percentage of free testosterone generally does not vary with age, but an absolute decrease in free testosterone was observed. This decline does not occur suddenly at menopause, but instead occurs gradually and continuously as a result of an age-related decrease in adrenal and ovarian androgen production. Thus, women begin to experience symptoms associated with menopause in the years immediately before menopause. The decrease in testosterone following menopause results from a combination of ovarian failure, decreased renal secretion and peripheral conversion. Also, for example, after oophorectomy, testosterone levels are reduced by about 50%. Signs or symptoms of testosterone deficiency include, for example, decreased bone mass, decreased physical discomfort or happiness, muscle weakness, fatigue, decreased libido, decreased sexual sensitivity and pleasure, and changes in cognition or memory.

  A “testosterone deficiency disorder effective” or “testosterone deficiency disorder effective amount” is used to treat or prevent a testosterone deficiency disorder in a mammal or to treat one or more of the symptoms associated with or related to a testosterone deficiency disorder in a mammal. The aim is to limit the amount of testosterone needed to alleviate to some extent. In women, examples include, but are not limited to, normalizing hypogonadism, improving sexual dysfunction, increasing libido, normalizing cholesterol levels, patients Normalizing abnormal electrocardiograms in the body to improve vasomotor symptoms, diabetic retinopathy, lowering insulin requirements in diabetics, lowering body fat percentage, normalizing glucose levels Reducing risk factors for cardiovascular disease, eg normalizing hypertension and treating obesity, preventing osteoporosis, osteopenia, vaginal dryness and thinning of the vaginal wall, menopausal Relieve symptoms and hot flashes, improve cognitive impairment, treat cardiovascular disease, Alzheimer's disease, dementia and cataract Prevent or reduce the incidence, treat or prevent or reduce the risk of cervical cancer, uterine cancer or breast cancer, eg treat or prevent depression, including postpartum depression Improving the effectiveness of in vitro fertilization or its failure, for example reducing the risk of improper embryo implantation in the uterus, treating or preventing premature menopause or reducing the risk of its occurrence Can be mentioned.

  The use of the term “about” in this disclosure means “approximately”, and the use of the term “about” can be effective and safe for dosages slightly outside the quoted ranges, as such Are shown to be included within the scope of the claims.

  The term “pharmaceutically acceptable” is used herein as an adjective, meaning that a modified noun is suitable for pharmaceutical use. The pharmaceutically acceptable cations include metal ions and organic ions. Illustratively, metal ions include, but are not limited to, suitable alkali metal salts, alkaline earth metal salts, and other physiologically acceptable metal ions. Exemplary ions include normal valence aluminum, calcium, lithium, magnesium, potassium, sodium and zinc. Illustratively, organic ions include protonated tertiary amines and quaternary ammonium cations such as, for example, trimethylamine, diethylamine, N, N′-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine. (N-methylglucamine) and procaine. Exemplary pharmaceutically acceptable acids include, but are not limited to, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, acetic acid, formic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitrate. Examples include acids, succinic acid, lactic acid, gluconic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, fumaric acid, propionic acid, aspartic acid, glutamic acid, benzoic acid and the like.

  The term “penetration enhancer” refers to an agent known to facilitate the delivery of a drug through the skin. These agents are also called accelerators, adjuvants and absorption enhancers, and are collectively referred to herein as “enhancers”. This class of agents includes those that have the ability to improve drug solubility and diffusivity, and alter the ability of the stratum corneum to retain moisture, soften the skin, improve skin permeability, Those having various mechanisms of action include those that act as penetration aids or hair follicle openers or that improve percutaneous absorption by altering the condition of the skin, such as the boundary layer. The penetration enhancer of the present invention is a functional derivative of a fatty acid, and examples thereof include an isosteric modification of a fatty acid, a non-acidic derivative of a carboxylic acid functional group of a fatty acid, or an isosteric modification thereof. In one embodiment, the functional derivative of a fatty acid is an unsaturated alkanoic acid in which the —COOH group is replaced with a functional derivative thereof, such as an alcohol, polyol, amide, and substituted derivatives thereof. The term “fatty acid” means a fatty acid having from 4 to 24 carbon atoms.

  Non-limiting examples of penetration enhancers include C8-C22 fatty acids such as isostearic acid, octanoic acid and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids; For example, ethyl oleate, isopropyl myristate, butyl stearate and methyl laurate; di (lower) alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; Polyethylene glycol, propylene glycol; 2- (2-ethoxyethoxy) ethanol; diethylene glycol monomethyl ether; poly Alkylaryl ethers of Chiren'okishido; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; dimethyl sulfoxide; glycerin; ethyl acetate; acetoacetate; N- alkylpyrrolidones; and terpenes, and the like.

  Thickeners used herein include anionic polymers such as polyacrylic acid (CARBOPOL® by C.Fandrich Specialty Polymers and Chemicals Division, Cleveland, Ohio), carboxymethylcellulose, and others. Additional thickeners, enhancers and adjuvants can generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., US Pharmacopeia / National Formulary.

  As used herein, the term “lower alcohol”, alone or in combination, means a linear or branched alcohol moiety containing from 1 to about 6 carbon atoms. In one embodiment, the lower alcohol contains 1 to about 4 carbon atoms, and in other embodiments, the lower alcohol contains 2 to about 3 carbon atoms. Examples of such alcohol moieties are methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, sec-butanol and tert-butanol.

  As used herein, the term “lower alkyl”, alone or in combination, means a straight or branched alkyl radical containing from 1 to about 6 carbon atoms. In one embodiment, the lower alkyl contains 1 to about 4 carbon atoms. Examples of such radicals are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl and tert-butyl.

  The composition of the present invention is used in a “testosterone deficiency disorder effective amount”. This means that the testosterone concentration is such that a therapeutic level of the drug is delivered over the period in which the transdermally delivered formulation is used. Such delivery depends on a number of variables, including the time period over which the individual dosage units are used, the therapeutic agent from the gel, such as the rate of testosterone efflux, the surface area of the application site, and others. The amount of therapeutic agent required can be determined experimentally based on the rate of drug efflux through the gel and skin when used with an enhancer and when not. However, the specific dose level of the therapeutic agent of the present invention for any particular patient depends on the activity of the specific compound used, the patient's age, weight, health status, sex and diet, time of administration, excretion rate It will be understood that this will depend on a variety of factors, including the concomitant medication, the severity of the particular disorder being treated and the mode of administration. In general, therapeutic dosage can be titrated to optimize safety and efficacy. In general, dose-response relationships from in vitro and / or in vivo studies can initially provide useful guidance regarding appropriate doses for patient administration. In general, animal model studies can be used for guidance on effective doses for menopause according to the present invention. With respect to therapeutic protocols, it should be understood that the dosage administered will depend on a number of factors including the particular agent being administered, the route of administration, the condition of the patient, etc. Generally speaking, it is desirable to administer an amount of compound effective to achieve a serum level commensurate with the concentration found to be effective in vitro, since such testing is Based on the assumption of having a predictive in vivo value. Thus, if a compound is found to exhibit in vitro activity at, for example, 10 ng / ml, it is desirable to administer an amount of the drug effective to provide a concentration of about 10 ng / ml in vivo. The determination of these parameters is well within the skill of the art. These considerations, as well as effective formulations and administration techniques, are known in the art and are described in standard textbooks.

  Serum testosterone levels can be measured using standard assay techniques to measure and determine a testosterone deficiency effective amount of testosterone delivered to a subject. For example, free serum testosterone levels are described in Sinha-Hikim et al., “Sensitive equilibrium for determination of free testosterone levels in healthy and HIV-infected women, which is fully incorporated herein by reference. Examined in The Use of a Sensitive Equilibrium Dialysis Method for the Measurement of Free Testosterone Levels in Healthy, Cycling Women and in HIV-Infected Women, 83 J. CLINICAL ENDOCRINOLOGY & METABOLISM, 1312-18 (1998) It can be measured by a recently validated highly sensitive equilibrium dialysis method.

In one embodiment of the invention, a method is provided for treating, preventing or reducing the risk of developing testosterone deficiency disorders in a female subject in need thereof. The method includes administering an amount of the composition to a region of the subject's skin (generally greater than about 5 cm ² ), which delivers a therapeutically effective amount of testosterone to the subject's serum. The composition comprises about 0.1% to about 10% testosterone, or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug, derivative; ethanol or About 30% to about 98% alcohol selected from the group consisting of isopropanol; about 0.1% to about 5% isopropyl myristate; about 0.1% to about 5% gelling agent; and balance water Can be included. The percentage of the composition is the weight ratio of the composition, and the total of the components of the composition is about 100% by weight. The composition is capable of releasing testosterone into the skin at a rate and duration that raises the testosterone serum concentration to at least about 3 pg testosterone / serum 1 ml within about 24 hours after administration. In one embodiment, the composition comprises about 1% to about 10% 0.1N sodium hydroxide.

  In one embodiment of the invention, the gelling agent is selected from the group consisting of polyacrylic acid and carboxymethylcellulose. In one embodiment, the gelling agent is polyacrylic acid present in an amount of about 1% by weight with the composition.

  In other embodiments of the invention, the composition weighs about 100 grams or less. In yet another embodiment, the composition weighs from about 1 gram to about 10 grams. In other embodiments, the composition weighs from about 4.4 grams to about 8.8 grams. In yet another embodiment, the composition weighs from about 2.5 grams to about 7.5 grams.

  In yet another embodiment of the invention, the composition is in the form of a gel.

  In yet another embodiment of the invention, an increase in serum testosterone concentration of at least about 5 ng / dL occurs in the subject per administration of about 0.1 gram of composition to the skin per day.

  In yet another embodiment of the invention, the composition is provided to the subject for daily administration at a dose of about 0.1 g to about 10 g. In other embodiments, the amount of the composition is a 0.44 g dose and delivers about 0.44 mg to about 44 mg of testosterone to the skin. In yet another embodiment, the amount of the composition is a 0.44 g dose and delivers about 2.2 mg to about 4.4 mg of testosterone to the skin. In other embodiments, the amount of the composition is a 8.8 g dose, delivering about 0.88 mg to about 88 mg of testosterone to the skin. In yet another embodiment, the amount of the composition is a 0.88 g dose and delivers 4.4 mg to about 8.8 mg of testosterone to the skin. In other embodiments, the amount of the composition is a 1.32 g dose and delivers about 1.32 mg to about 132 mg of testosterone to the skin. In yet another embodiment, the amount of the composition is a 1.32 g dose and delivers 6.6 mg to about 13.2 mg of testosterone to the skin.

  In one embodiment of the invention, administration of the composition results in steady testosterone levels by the third day of treatment.

  In other embodiments of the present invention, the composition is provided to the subject in one or more packets, and the packets can include a polyethylene liner between the composition and the packet inner surface. A packet can hold a unit dose or multiple doses.

  In other embodiments, the composition is infused (eg, with a hand pump) from a robust multi-dose container having, for example, a larger foil packet of the composition in the container. Such larger packets can also include a polyethylene liner as above. In one embodiment, the multi-dose container includes an airless pump that includes a polyethylene pouch in a canister with a hand pump inserted. In one embodiment, the polyethylene pouch contains 44 g or 88 g of product. In one embodiment, the pump is prepared prior to use, for example, by pressing down the pump completely three times and discarding the gel. In one embodiment, the pump includes sufficient product to allow for the preparation and a set number of accurate doses. In one embodiment, one full pump depression delivers 1.25 g of testosterone gel. In this embodiment, the 3.75 g dose of gel requires 3 pump depressions. A 5 g dose of gel requires 4 pump depressions. A 7.5 g dose of gel requires 6 pump depressions. A 10 g dose of gel requires 8 pump depressions, and so on. Of course, any amount of testosterone gel suitable for delivering the desired dose can be delivered with a single pump depression.

  In yet another embodiment of the invention, the composition is provided as a separate element from the kit.

  In yet another embodiment of the invention, the composition is administered once, twice or three times daily, or as many times as necessary to achieve a therapeutic effect.

  In other embodiments of the invention, the composition further comprises about 0.01% to about 69% of a therapeutic agent comprising an agent that inhibits the synthesis of sex hormone binding globulin, progesterone, progestin, or estrogenic hormone. In yet another embodiment, the therapeutic agent comprises about 1% to about 10% of the composition. In other embodiments of the invention, the therapeutic agent is progesterone. In yet another embodiment, the serum concentration of progesterone increases to at least about 1 ng progesterone / ml serum within about 24 hours of administering the composition to the subject. In yet another embodiment of the invention, the therapeutic agent is estrogen. In other embodiments, the serum concentration of estrogen increases to at least 60 pg estrogen / ml serum within about 24 hours of administration.

  In one embodiment of the present invention, there is provided a method for treating, preventing or reducing the risk of developing testosterone deficiency disorder in a female subject in need thereof, the method having or having testosterone deficiency disorder. Identifying a female subject at risk of developing and administering an amount of a composition to an area of the subject's skin, the amount delivering a therapeutically effective amount of testosterone to the serum of the subject, As a result, testosterone deficiency disorder or the risk of its onset is reduced. In one embodiment, the composition comprises about 0.1% to about 10% testosterone, or a salt, ester, amide, enantiomer, isomer, tautomer, prodrug, or derivative thereof; ethanol or isopropanol About 30% to about 98% alcohol selected from the group consisting of; about 0.1% to about 5% gelling agent; and balance water, these percentages being by weight of the composition; The total of the components of the composition is about 100% by weight. In one embodiment, the sum of the ingredients is less than 100% and a sufficient amount of water is added to make it 100%. In one embodiment, the composition is capable of releasing testosterone into the skin at a rate and duration that increases the testosterone serum concentration to at least about 3 pg testosterone / ml serum within about 24 hours after administration. In one embodiment, the composition comprises about 1% to about 10% 0.1N sodium hydroxide.

  In another embodiment of the invention, a method is provided for delivering an effective amount of testosterone deficiency disorder of testosterone to the serum of a female subject in need thereof, wherein the method comprises about 0.1% to about 0.1% of the subject's skin. 10% testosterone or salts thereof, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, derivatives; from about 30% selected from the group consisting of ethanol or isopropanol About 0.1% to about 5% isopropyl myristate; about 0.1% to about 10% 0.1N sodium hydroxide; about 0.1% to about 5% gelling agent Including contacting with a composition comprising balanced water, these percentages being by weight of the composition, the total of the components of the composition being about 100% by weight. In one embodiment, the sum of the ingredients is less than 100% and a sufficient amount of water is added to make it 100%. In one embodiment, the composition is capable of releasing testosterone into the skin at a rate and duration that increases the testosterone serum concentration to at least about 3 pg testosterone / ml serum within about 24 hours after administration.

  In yet another embodiment of the invention, there is provided a method of administering an effective amount of testosterone deficiency disorder of testosterone to the serum of a female subject in need thereof, the method comprising from about 0.1% to about 10% testosterone. Or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug, derivative; about 30% to about 98% selected from the group consisting of ethanol or isopropanol A medicament comprising: about 0.1% to about 5% isopropyl myristate; about 0.1% to about 10% 0.1N sodium hydroxide; and about 0.1% to about 5% gelling agent. Providing a composition and delivering the testosterone to the subject's serum such that the composition achieves a serum concentration of at least 3 pg testosterone / ml serum within about 24 hours after administration. In an amount sufficient in order, and a administering to the skin of a subject. These percentages are weight ratios to the composition, and the total of the components of the composition is about 100% by weight. In one embodiment, the sum of the ingredients is less than 100% and a sufficient amount of water is added to make it 100%.

  Steroids in the testosterone synthesis system useful in the methods, kits, combinations and compositions of the present invention include steroids in the testosterone anabolic or catabolic pathway. In a broad aspect of the invention, the active ingredient used in the composition includes anabolic steroids such as androisoxazole, borasterone, crostebol, ethylestrenol, formyldienolone, 4-hydroxy-19-nortestosterone. , Methenolone, methyltrienolone, nandrolone, oxymesterone, quinbolone, stenbolone, trenbolone; androgenic steroids such as boldenone, fluoxymesterone, mestanolone, methesterolone, metandrostenolone, 17α-methyltestosterone, 17α-methyl-testosterone 3-cyclopentyl enol ether, norethanedrone, normethandrone, oxandrolone, oxymetholone, plasterone, stanlorone, stanozoro , Dihydrotestosterone, testosterone; and progestogens such as anagestone, chlormadinone acetate, dermadinone acetate, demegestone, dimethosterone, dihydrogesterone, ethynylestrenol, ethisterone, ethinodiol, ethinodiol diacetate, flurogestone acetate, guestden, caprolate guestnolone, Haloprogesterone, 17-hydroxy-16-methyleneprogesterone, 17α-hydroxyprogesterone, caproic acid 17α-hydroxyprogesterone, medrogestone, medroxyprogesterone, megestrol acetate, melengestrol, norethindrone, norethindrone acetate, norethinodrel, norgesterone, norgestrel, norgestrel , Norgestrienon 19-norprogesterone, norbinisterone, pentagestrone, progesterone, promegestone, quingestrone and trengestone; and all salts, esters, hydrates, amides, enantiomers, isomers, tautomers of these compounds Body, polymorph, prodrug or derivative. (Based on the list provided by The Merck Index, Merck & Co., Rahway, N.J. (1998)). Combinations of the above steroids can be used.

  In one embodiment, testosterone is formulated as an aqueous alcohol gel. In other embodiments, the gel comprises one or more lower alcohols such as testosterone, ethanol or isopropanol, penetration enhancers, thickeners (also known as gelling agents) and water. In one embodiment, the gel further comprises a hydroxide releasing agent such as sodium hydroxide. In addition, the present invention can optionally include salts, mitigating agents, stabilizers, antimicrobial substances, fragrances and propellants.

  Non-limiting examples of penetration enhancers include C8-C22 fatty acids such as isostearic acid, octanoic acid and oleic acid; C8-C22 fatty alcohols such as oleyl alcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acids; For example, ethyl oleate, isopropyl myristate, butyl stearate and methyl laurate; di (lower) alkyl esters of C6-C22 diacids such as diisopropyl adipate; monoglycerides of C8-C22 fatty acids such as glyceryl monolaurate; Polyethylene glycol, propylene glycol; 2- (2-ethoxyethoxy) ethanol; diethylene glycol monomethyl ether; poly Alkylaryl ethers of Chiren'okishido; polyethylene oxide monomethyl ether; polyethylene oxide dimethyl ether; dimethyl sulfoxide; glycerin; ethyl acetate; acetoacetate; N- alkylpyrrolidones; and terpenes and the like.

  Thickeners (also known as gelling agents) used herein include anionic polymers such as polyacrylic acid (CARBOPOL® by BF Goodrich Specialty Polymers and Chemicals Division of Cleveland, Ohio), carboxypolymethylene , Carboxymethyl cellulose, and other derivatives of Carbopol® polymer, such as Carbopol® Ultrez 10, Carbopol® 940, Carbopol® 941, Carbopol® 954, Carbopol® 95 ) 980, Carbopol® 981, Carbopol® ETD 2001, Carbopol® EZ-2 and Carbopol® EZ-3, and other polymers such as Pemulen®, polymeric emulsifiers And Noveon® polycarbophil. Additional thickeners, enhancers and adjuvants can generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., US Pharmacopeia / National Formulary.

  In one embodiment, the formulations of the invention deliver from about 0.5 mg to about 50 mg of testosterone per dosage unit or equivalent thereof to a subject. In other embodiments of the invention, the formulation delivers from about 0.5 mg to about 25 mg of testosterone per dosage unit or equivalent thereof to the subject. In other embodiments of the invention, the formulations of the invention deliver from about 4 mg to about 15 mg of testosterone per dosage unit or equivalent thereof to a subject. In yet another embodiment of the present invention, the formulations of the present invention comprise about 4.4 mg testosterone, or about 8.8 gm testosterone, or about 13.2 mg testosterone per dosage unit for a subject, or Deliver its equivalent. Thus, for example, a testosterone gel, ointment, cream or patch formulated for once daily administration can contain about 4.4 mg, or about 8.8 mg, or about 13.2 mg of testosterone.

  In one embodiment, the formulation is a gel, ointment, cream or patch consisting of testosterone, a penetration enhancer such as isopropyl myristate, a thickener such as Carbopol, a lower alcohol such as ethanol or isopropanol, and water. In other embodiments, the formulation is a gel, ointment, cream or patch and is comprised of the following approximate percentages of material:

  In one embodiment, in a 100 g composition, the gel, ointment, cream or patch is about 0.01 g to about 15 g testosterone, about 0.01 g to about 50 g penetration enhancer, about 0.1 g to about 50 g gel. And about 30 g to about 98 g of a lower alcohol. In other embodiments, in a 100 g composition, the gel, ointment, cream or patch is about 0.1 g to about 10 g testosterone, about 0.1 g to about 5 g penetration enhancer, about 0.1 g to about 5 g. The gelling agent can include from about 45 g to about 90 g of lower alcohol.

  In one embodiment, the composition is sodium hydroxide or triethanolamine or potassium hydroxide, or an amount thereof sufficient to assist the gelling agent during gel formation, as is known in the art. A gel, ointment, cream or patch further comprising a combination. In one embodiment, the solution of sodium hydroxide is, for example, 0.1N sodium hydroxide solution, 0.2N sodium hydroxide solution, 0.5N sodium hydroxide solution, 1.0N sodium hydroxide solution, 1.5N hydroxide. Sodium solution, 2.0N sodium hydroxide solution, or any other suitable solution that provides a sufficient amount of sodium hydroxide to the composition is used. In one embodiment, the composition comprises about 1% to about 10% 0.1N sodium hydroxide.

  In other embodiments, the pharmaceutical composition is about 0.5% to about 10% testosterone, about 30% to about 98% alcohol, such as ethanol or isopropanol, about 0.1% to about 5% isopropyl myristate, About 0.1% to about 5% gelling agent and balance water. The percentage of ingredients is a weight ratio to the composition.

  In yet another embodiment, the pharmaceutical composition comprises testosterone in an hydroalcoholic gel. Testosterone is about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7% by weight of the composition. %, About 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.1%, 2.2%, 2.3%, 2.4%, About 2.5%, about 2.6%, about 2.7%, about 2.8%, about 2.9%, about 3%, about 3.1%, about 3.2%, about 3.3 %, About 3.4%, about 3.5%, about 3.6%, about 3.7%, about 3.8%, about 3.9%, about 4%, about 4.1%, about 4% .2%, about 4.3%, about 4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about 5%, About 5.1%, about 5.2%, about 5.3%, about 5.4%, about .5%, about 5.6%, about 5.7%, about 5.8%, about 5.9%, about 6%, about 6.1%, about 6.2%, about 6.3%, About 6.4%, about 6.5%, about 6.6%, about 6.7%, about 6.8%, about 6.9%, about 7%, about 7.1%, about 7.2 %, About 7.3%, about 7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about 8%, about 8 0.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about 8.6%, about 8.7%, about 8.8%, about 8.9 %, About 9%, about 9.1%, about 9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about 9 .8%, about 9.9%, about 10%, about 10.1%, about 10.2%, about 10.3%, about 10.4%, about 10.5%, about 10.6%, About 10.7%, about 10.8%, about 10.9%, about 11% About 11.1%, about 11.2%, about 11.3%, about 11.4%, about 11.5%, about 11.6%, about 11.7%, about 11.8%, about 11 9.9%, about 12%, about 12.1%, about 12.2%, about 12.3%, about 12.4%, about 12.5%, about 12.6%, about 12.7%, About 12.8%, about 12.9%, about 13%, about 13.1%, about 13.2%, about 13.3%, about 13.4%, about 13.5%, about 13.6 %, About 13.7%, about 13.8%, about 13.9%, about 14%, about 14.1%, about 14.2%, about 14.3%, about 14.4%, about 14 0.5%, about 14.6%, about 14.7%, about 14.8%, about 14.9% or about 15%. The enhancer of this embodiment is isopropyl myristate, which is about 0.5%, about 0.65%, about 0.75%, about 0.85%, about 0.95% by weight of the composition. , About 1%, about 2%, about 3%, about 4% or about 5%. The pharmaceutical composition is about 70%, about 71%, about 71.4%, about 71.8%, about 72%, about 72.3%, about 72.5%, about 7% by weight with respect to the composition. Also included are C1-C4 alcohols present at concentrations of 72.7%, about 73%, about 73.5%, about 74%, about 74.5%, about 75% or about 75%. Furthermore, the pharmaceutical composition comprises polyacrylic acid and / or carboxymethylcellulose as a gelling agent. In one embodiment, the gelling agent is polyacrylic acid present at a concentration of about 1% by weight with the composition.

  In one embodiment, the gel is composed of the following approximate amounts of material:

  Those skilled in the art will appreciate that the components of this formulation can vary in amount and still remain within the spirit and scope of the present invention. For example, the composition comprises about 0.1 to about 10.0 g testosterone, about 0.1 to about 5.0 g CARBOPOL, about 0.1 to about 5.0 g isopropyl myristate, about 30.0 to about 98. 0.0 g ethanol and balance water may be included.

  In yet another embodiment, the composition comprises a testosterone in an amount greater than 0.01% by weight relative to the composition, a penetration enhancer in an amount greater than about 0.1%, and an increase in an amount greater than about 0.1%. Contains a sticky agent and lower alcohol in an amount greater than about 30%. The gel is rubbed once a day onto clean, dry skin on the upper outside of the thigh and waist. After application, the gel is allowed to air dry. The patient cleans his hands. Application of the gel results in elevated testosterone levels with a desirable pharmacokinetic profile similar to that of normal women. Gels are therefore useful for treating several conditions or diseases in women.

  In one embodiment, about 0.44 g of gel is applied to the subject's skin to deliver about 4.4 mg of testosterone to the skin. In one embodiment, about 0.88 g of gel is applied to the subject's skin and about 8.8 mg of testosterone is delivered to the skin. In other embodiments, about 1.32 g of gel is applied to the subject's skin and about 13.2 mg of testosterone is delivered to the skin.

  Achieving the target delivery dose exhibited by testosterone gel can be estimated from the pharmacokinetics of testosterone gel in men. The average serum concentration (Cavg) values for men after applying various amounts of gel to the upper body are shown in Table 5 below.

  Based on the results obtained in men, a 0.5 gram testosterone gel dose delivers about 300 μg of testosterone per day.

  Illustratively, for adult females, an effective amount of testosterone deficiency disorder of testosterone per daily dose typically delivers about 100 μg to about 150 μg to about 260 μg to about 300 μg to about 776 μg of testosterone per day to the serum. Thus, for example, to achieve a serum blood concentration of about 100 μg testosterone, RELIBRA ™ (applicant's proprietary female gel product trademark) is administered in an amount of about 0.17 g / day, About 1.7 mg / day of testosterone is delivered to the skin, about 0.1 mg of which is absorbed. Alternatively, to achieve a serum blood concentration of about 150 μg testosterone, RELIBRA is administered in an amount of about 0.25 g / day, which delivers about 2.5 mg / day of testosterone to the skin, of which about 0.15 mg Is absorbed. Alternatively, to achieve a serum blood concentration of about 259 μg testosterone, RELIBRA is administered in an amount of about 0.44 g / day, which delivers 4.4 mg / day of testosterone to the skin, about 0.259 mg of which Absorbed. Alternatively, to achieve a serum blood concentration of about 300 μg testosterone, RELIBRA is administered in an amount of about 0.5 g / day, which delivers 5 mg / day of testosterone to the skin, about 0.3 mg of which is absorbed. The Alternatively, to achieve a serum blood concentration of about 150 μg testosterone, RELIBRA is administered in an amount of about 0.25 g / day, which delivers about 2.5 mg / day of testosterone to the skin, of which about 0.15 mg Is absorbed. Alternatively, to achieve a serum blood concentration of about 776 μg testosterone, RELIBRA is administered in an amount of about 1.32 g / day, which delivers 13.2 mg / day of testosterone to the skin, about 0.776 mg of which Absorbed.

  In one embodiment, the present invention using testosterone is combined with a pharmacologically effective amount of an estrogenic hormone, such as estradiol.

  Estrogenic hormones that are useful in the methods, kits, combinations and compositions of the present invention include several compounds that are chemical modifiers generated from natural estrogens to enhance their therapeutic effects when administered orally. Can be mentioned. These include the steroids ethinyl estradiol, mestranol and quinestrol. In addition to these steroidal estrogens, various nonsteroidal compounds having estrogenic activity have been synthesized and used clinically. These include diethylstilbestrol, chlorotrianicene and metallenestryl. Some commonly used estrogen mean replacement doses are shown in Table 6 below.

  Oral administration of estrogens often results in adverse effects on the liver. These effects on the liver can be minimized by routes of administration that avoid first-pass liver exposure, such as topical (vaginal) or transdermal administration provided by the present invention.

  The decrease in testosterone production by women is due to several factors, including, but not limited to, the use of oral contraceptives, surgery, such as resection of the uterus (hysterectomy) or one resection of the ovary (ovariectomy) / Ovariectomy), estrogen replacement therapy in postmenopausal women, premature ovarian failure, adrenal dysfunction, eg primary adrenal dysfunction, corticosteroid-induced adrenal suppression, panhypopituitarism, and chronic diseases For example, systemic lupus erythematosus, rheumatoid arthritis, human immunodeficiency virus (HIV) infection, chronic obstructive pulmonary disease and end-stage renal disease.

  Physiological and mental disorders associated with female testosterone deficiency include, but are not limited to, decreased libido and sexual performance, decreased bone mineral density and related markers, decreased body components, and human immunodeficiency virus exhaustion There are syndromes, cognitive decline, reduced emotion and self-esteem, reduced muscle mass and performance, premenstrual syndrome, central nervous system disorders and autoimmune diseases.

  Without wishing to be bound by theory, the multifaceted role of androgens as neurohormones appears to reflect the widespread distribution of specific receptors in the brain. Regions where such receptors are located include the cortex, pituitary gland, hypothalamus, preoptic area, and thalamus, cerebellar tonsils and brain stem. Androgen receptors not only co-exist with estrogen and progesterone receptors, but are also found in areas that are not. The action of androgens is mediated through receptors, but is also mediated through the aromatization of testosterone to estradiol by the enzyme aromatase, resulting in an estrogen-mediated action.

  Although there are well-defined patient populations that are clearly deficient in testosterone production and associated symptoms described, such populations are contemplated as being within the scope of the present invention. These populations include those associated with specific etiologies such as ovarian (chemotherapy, radiation therapy, ovariectomy), adrenal (adrenal dysfunction, adrenalectomy), hypothalamic pituitary (pituitary). Hypofunction), drug-related (corticosteroids, antiandrogens, oral contraceptives, oral estrogen replacement therapy) and / or idiopathic. (See Braunstein, G. et al., Fertility and Sterility, Vol. 77, No. 4, April 2002, pages 660-665).

  Patients that can be treated with the present invention include those at risk of developing a testosterone deficiency disorder, or patients who are currently experiencing a testosterone deficiency disorder event. Standard testosterone deficiency disorder risk factors are known to the average physician practicing in the relevant medical field. Patients identified as having one or more risk factors known in the art at risk of developing a testosterone deficiency disorder, as well as those who already have a testosterone deficiency disorder are at risk of having a testosterone deficiency disorder event. It shall be included in the group of possible people.

  Further, the contemplated methods, kits, combinations and compositions of the present invention can be used in women, such as women who are deficient in testosterone production, or when related symptoms associated with deficiency in testosterone production are clinically evident. Helps to treat, testosterone deficiency. Examples include ovariectomized / hysterectomized women, menopausal women on estrogen replacement therapy, women taking oral contraceptives, women ovariectomized, women with premature ovarian failure, women with adrenal dysfunction, cortico Women with steroid-induced adrenal suppression, women with panhypopituitarism, women with primary adrenal dysfunction, and chronic diseases such as systemic lupus erythematosus, rheumatoid arthritis, human immunodeficiency virus (HIV) Women with infection, chronic obstructive pulmonary disease and end-stage renal disease are included.

  In one embodiment of the invention, the methods, kits, combinations and compositions are performed at a younger age, particularly at a younger age before the operation is natural before menopause, especially for women who have undergone surgery, such as bilateral ovariectomy with hysterectomy. Helpful in treating women. In the United States alone, over 250,000 women undergo a combined ovariectomy / hysterectomy each year, and they are clearly deficient in testosterone production. Serum testosterone levels in women who have undergone ovariectomy are generally reduced by 50% compared to preoperative levels, but in some cases, levels may remain in the normal reference range (approximately 20-80 ng / dL). is there. Estrogen and progesterone levels, mainly dependent on ovarian secretion, are also significantly reduced after ovariectomy. The resulting multiple hormone deficiency states are associated with vasomotor symptoms, high turnover osteoporosis and female sexual dysfunction. Estrogen replacement therapy is the standard for the treatment of vasomotor symptoms and osteoporosis in ovariectomized / hysterectomized women, but the accompanying testosterone therapy for the treatment of the effects of estrogen replacement therapy on female sexual dysfunction and bone metabolism Is not instructed. Such women are within the scope of the present invention.

  In other embodiments of the invention, the methods, kits, combinations and compositions are useful in the treatment of menopausal women. In contrast to the ovariectomized state, the post-menopausal ovary can continue to synthesize testosterone in the interstitial tissue, not necessarily lower than the pre-menopausal period. In some menopausal women, testosterone levels increase as a result of the interstitial response to elevated luteinizing hormone levels, while in others, testosterone levels decrease or are the same. Since estrogen replacement therapy lowers luteinizing hormone levels, testosterone secretion by the ovaries is expected to decrease in postmenopausal women receiving estrogen replacement therapy. In oral estrogen replacement therapy formulations, a drop in testosterone levels may be obscured by an accompanying increase in sex hormone binding globulin levels that reduce testosterone clearance. However, it is discovered that free and / or bioavailable testosterone levels are lower in postmenopausal women receiving oral estrogen replacement therapy. Although the effect of transdermal estrogen replacement therapy on androgen / luteinizing hormone status in postmenopausal women has not been studied, a decrease in total and free testosterone levels associated with a decrease in luteinizing hormone levels is also expected. Testosterone deficiency appears to be a contributing factor because many menopausal women experience symptoms of female sexual dysfunction that are not ameliorated by estrogen replacement therapy, so this group of women is within the scope of the present invention .

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women using oral contraception. Oral contraception is the most common method of contraception among young people, and about 46% of all sexually active populations use it. The most common types of oral contraceptives include estrogens and progestins and have been found to be about 99% effective. Thus, almost half of all premenopausal women (<44 years) may be taking oral contraceptives. Compared to healthy “cycled” women, testosterone levels of women treated with estrogen-containing oral contraceptives are significantly lower, especially when compared to the normal cycle pre-ovulation, where testosterone levels are highest. This effect is due to luteinizing hormone suppression caused by oral contraceptives and is similar to the effect of estrogen replacement therapy described above. Also, the use of oral contraceptives generally increases sex hormone-binding globulin levels in women, causing increased testosterone binding, resulting in decreased free testosterone levels. The psychosexual aspect of cognition is affected by lower testosterone levels and may be related to the reduction in libido observed clinically in some women who use oral contraceptives.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women who have undergone oophorectomy, eg, with surgery, chemical means, radiation or gonadotropin releasing hormone antagonists. Such surgery leads to a decrease in ovarian androgen product.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women with premature ovarian failure. Premature ovarian failure, such as Turner syndrome or those associated with autoimmune or idiopathic destruction of the ovary, is associated with impaired testosterone production.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in treating women with reduced adrenal function. The decrease in adrenal function that can result from various causes represents another category of patients with about 50% reduction in testosterone production. Primary adrenal cortex deficiency or Addison's disease is a rare endocrine disorder with multiple etiologies including tuberculosis and fungal infection. The estimated prevalence in women is about 5 per 100,000. Addison's disease can be life threatening due to lack of secretion of glucocorticoids and mineralocorticoids. Although some researchers have noted associated testosterone deficiency, replacement therapy is often ignored. Since corticotropin appears to be a major stimulator of adrenal androgen production, deficiency of corticotropin secretion can also cause testosterone deficiency in women. This may result from pituitary disease or surgery, such as secondary adrenal cortex deficiency, or may occur as a pharmacological effect of exogenous corticosteroid administration that can suppress adrenocorticotropic hormone secretion.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women who have been administered long-term corticosteroid therapy. Long-term corticosteroid therapy is used for a variety of conditions, including rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, transplant immunosuppression, asthma, and others. Corticosteroid-induced adrenal suppression may therefore represent the largest group of patients with deficient adrenal androgen production. Androgen deficiency is recognized as a contributing factor to corticosteroid-induced osteoporosis. By stimulating bone formation (osteoblast activity), testosterone supplementation is beneficial in the treatment of corticosteroid-induced osteoporosis in premenopausal women and also in estrogen replacement therapy when treating menopausal women It is. In women with autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus, testosterone deficiency can contribute to the tendency to produce the underlying autoantibodies, which is seen in various animal models of autoimmune diseases It was. Testosterone supplementation can therefore help improve the autoimmune disease process itself. Despite these considerations, the potential therapeutic benefit of testosterone supplementation in the treatment of women suppressed with corticosteroids has been largely ignored.

  In other embodiments of the invention, the methods, kits, combinations and compositions are useful in the treatment of panhypopituitarism women. Panhypopituitarism for any cause is accompanied by severe testosterone deficiency due to disruption of androgen secretion by the ovaries and adrenal glands.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women with primary adrenal insufficiency. Primary adrenal insufficiency is associated with testosterone deficiency.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of women with chronic diseases. Chronic disease in women is accompanied by a decrease in circulating testosterone levels. Glucocorticoid administration suppresses androgen production by the adrenal glands by their inhibitory effect on adrenal corticotropin secretion. Furthermore, glucocorticoids also have an inhibitory effect at all levels of the hypothalamic pituitary ovary axis.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of human immunodeficiency virus positive women. In contrast to human immunodeficiency virus-positive men who commonly have testosterone deficiency, it is not known whether human immunodeficiency virus-positive women develop testosterone deficiency. Amenorrhea appears to increase in women with acquired immunodeficiency syndrome (AIDS), which may indicate a decrease in ovarian steroidogenesis. Due to cytomegalovirus infection, tuberculosis and / or fungal infection, adrenal function may be deficient in patients with acquired immune deficiency syndrome. Megestrol acetate, a progesterone agent used to promote appetite in human immunodeficiency virus-infected individuals, appears to suppress gonadotropins and reduce testosterone levels in women, similar to its effects in men To do. In addition, as noted above in normal women, the use of oral contraceptives by human immunodeficiency virus positive women also reduces testosterone levels. Physiological testosterone supplementation can be used as an anabolic agent to treat / prevent wasting syndrome in women and to enhance quality of life.

  The methods, kits, combinations and compositions of the present invention are also useful for treating a number of physiological and mental parameters associated with testosterone deficiency in women, such as increased libido and sexual performance. , Improved dysfunction, increased bone mineral density and related markers, improved body composition, prevention of human immunodeficiency virus exhaustion syndrome, improved cognitive ability, improved emotion and self-esteem, improved muscle mass and performance, premenstrual syndrome Treatment, central nervous system disorders, and autoimmune diseases.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of female libido. Testosterone levels clearly affect female libido. Over the last few decades, several correlation studies have shown that higher testosterone levels result in less sexual avoidance, more sexual satisfaction, more sexual thinking, more sexual behavior onset, higher levels It was found to be associated with sexual interest and desire, as well as expectations of more sexual behavior. Recently, a correlation between libido and testosterone was discovered in a subset of human immunodeficiency virus positive women.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment of female sexual performance. Studies have shown that testosterone affects female sexual performance. Correlative studies show that testosterone is associated with higher sexual arousal, as measured by vascular congestive responses to erotic images, increased masturbation frequency, increased sexual intercourse frequency and more sexual partners I found Other correlation studies have also shown that testosterone is associated with reduced vaginal atrophy.

  In other embodiments of the invention, the methods, kits, combinations and compositions are useful for treating female sexual dysfunction in women. Surgical menopause performed prior to natural menopause, namely total abdominal hysterectomy and bilateral tubal oophorectomy, is associated with a significant number of female sexual dysfunction syndromes that are not alleviated by conventional estrogen replacement therapy. Cause in women. Sexual components of this syndrome include decreased libido, decreased excitement, and decreased ability to achieve orgasm. Spiritual factors include a general decrease in energy loss, depressive feelings and happiness. These include classic estrogen deficiency symptoms of vaginal atrophy, reduced lubrication, hot flashes and emotional burden that can adversely affect sexual function and psychogenic health in postmenopausal women who have not received sufficient estrogen replacement therapy Can be generally identified. Rather than estrogen deficiency, the hormonal basis of this syndrome is attributed to the testosterone deficiency state resulting from the lack of production of testosterone and its precursors by the ovaries.

  In one study, the effects of testosterone in women with surgically induced postmenopausal sexual dysfunction were evaluated using transdermal patches. 75 women aged 31-56 years who had undergone oophorectomy and hysterectomy were equine conjugated estrogens (orally at least 0.625 mg / day) and, in random order, 150 μg testosterone and 300 μg testosterone per day Were transdermally administered for 12 weeks. Prognostic measures included Brief Index of Sexual Functioning for Women (BISF), Psychological Well-Being Index (PGWI) and sexual function diary scores performed over the phone. Mean (± standard deviation) serum free testosterone concentrations range from 1.2 ± 0.8 pg / mL during placebo treatment to 3.9 ± 2.4 pg / day during treatment with 160 and 300 μg of testosterone, respectively. increased to mL and 4.9 ± 4.8 pg / mL (normal range, 1.3-6.8 pg / mL). Despite considerable placebo response, higher testosterone doses resulted in a further increase in the score of frequency of sexual behavior and pleasure orgasm in the Brief Index of Sexual Functioning for Women (P = 0 in both comparisons with placebo) .03). At higher doses, the percentage of women who were sexually fancied, masturbated, or sexually intercourse at least once a week increased 2-3 fold from baseline. Higher doses also improved Psychological Well-Being Index positive well-being, depressed feelings, and composite scores (P = 0.04, P = 0.04, respectively, compared to placebo), but based on telephone Diary scores did not increase significantly.

  In other embodiments of the invention, testosterone therapy is combined with estrogen therapy. Studies show that testosterone and estrogen supplementation result in increased libido, frequency of sexual fantasies, sexual arousal and intercourse or orgasm compared to those who received estrogen alone or placebo Women who received testosterone in addition to estrogen were reported to experience further increases in libido, activity, satisfaction, pleasure, fantasies, orgasms and associations compared to women who received estrogen alone. It was. Treatment with Premarin and methyltestosterone resulted in a significant increase in masturbation pleasure reporting. Treatment with estrogen and methyltestosterone results in increased sexual interest as well. More recently, transcutaneous testosterone treatment in women after ovariectomy has been found to improve sexual function and mental well-being. Even without estrogen administration, testosterone administration alone is considered to have therapeutic benefit. For example, hypothalamic amenorrheic women show increased vaginal vascular congestion with treatment with testosterone compared to placebo.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful for treating reduced bone density in women. Another physiological parameter associated with testosterone administration in women is a reduction in bone mineral density. Several correlation studies have shown that increased testosterone levels are associated with increased bone mineral density. Higher levels of bioavailable testosterone were found to be associated with higher bone mineral density in the female ultradistal ribs. Women with polycystic ovary syndrome had neck bone mineral density that was positively correlated with free testosterone levels. Upper body bone mineral density was significantly correlated with testosterone. A cross-sectional analysis of female sex hormone concentrations and bone mineral density recruited for a prospective study of risk factors for osteoporosis found a significant positive correlation between testosterone and bone mineral density. Other studies included an age-stratified specimen of 304 women and found a correlation coefficient between bone mineral density and testosterone as shown in Table 7 below.

  Similar to libido and sexual ability, testosterone is often administered in combination with estrogen to prevent bone loss or increase bone mineral density. For example, in one cross-sectional study, subcutaneous estradiol (75 mg) and testosterone (100 mg) were found to prevent osteoporosis and maintain normal bone mineral density in postmenopausal women. In other studies, the effects of single-dose estrogen in menopausal women were inferior to those of estrogen plus androgen. The serum markers of osteogenesis in the estrogen-only group decreased, but the osteogenic markers of women treated with the combination of estrogen and testosterone increased. Similarly, estrogen and testosterone supplementation with implant pellets can increase bone mass over estrogen implants alone, increase bone mineral density by 5.7% in the spinal column, and increase by 5.2% in the femoral neck region. Indicated. Treatment with estrogen and methyltestosterone also results in an increase in spinal and lumbar bone mineral density. It has also been reported that orally administered estrogens and methyltestosterone prevent bone loss and increase bone mineral density in the spine and lumbar region.

  In other embodiments of the invention, the methods, kits, combinations and compositions are useful in the treatment of female body components. Testosterone has been associated with improved body composition in women. Testosterone was positively correlated with body mass index, and exogenous androgens affected body composition and local body fat distribution in obese menopausal women. Other researchers have found an increase in fat-free mass and a reduction in the ratio of fat mass to fat-free mass in postmenopausal women treated with concurrent estrogen and testosterone therapy. Thus, administration of testosterone to normal women or women with testosterone deficiency may have therapeutic improvements in body components.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions are useful in treating or preventing human immunodeficiency virus wasting syndrome in women. In recent years, researchers have found that administration of testosterone to women infected with human immunodeficiency virus may treat or prevent human immunodeficiency virus exhaustion syndrome. Using tracer-like methods, lower levels of free testosterone were found in women with human immunodeficiency virus infection. For example, testosterone supplementation with a patch delivering 150 μg / day of testosterone to human immunodeficiency virus-infected women resulted in a 4% weight gain in 12 weeks. In addition, the patient's quality of life has improved. Thus, testosterone administration can be used as a method to prevent wasting in women suffering from acquired immune deficiency syndrome or related disorders.

  In yet another embodiment of the invention, the methods, kits, combinations and compositions treat female short term and long term memory and other higher order cognitive functions, including those resulting from central nervous system disorders, for example. Or help to prevent. Sex steroids are important for short and long term memory and other higher cognitive functions. Menopausal women who received testosterone in addition to estrogen after ovariectomy had higher scores in two trials of short-term memory, one trial of long-term memory, and one trial of logical reasoning. Testosterone administration has been reported to be associated with better visual spatial function and verbal techniques. Women with high testosterone levels scored higher on special / mathematical tasks than women with low testosterone levels. Women with high Mini-Mental State Examination scores had significantly higher mean concentrations of total testosterone and bioavailable testosterone. Testosterone levels are also related to fluency of words. Again, the benefit of testosterone administration for cognitive parameters can be optimized by concurrent estrogen administration. For example, subcutaneous implants of estradiol (40 mg) and testosterone (100 mg) showed increased concentrations.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful in the treatment or prevention of emotional or self-esteem disorders in women. Parameters associated with female testosterone serum levels are emotion and self-esteem. Menopausal women who received estrogen and testosterone were more calm, enthusiastic and energetic than those who received estrogen alone. Similarly, testosterone levels are positively correlated with self-esteem. Thus, testosterone therapy is thought to improve emotion when used alone or in combination with estrogens.

  In other embodiments of the invention, the methods, kits, combinations and compositions serve to increase muscle size and ability in women. Androgens and anabolic steroids have long been used to increase muscle size and ability in men. Researchers also recently discovered that testosterone is an important determinant of larger muscles in women with polycystic ovary syndrome. Thus, administration of testosterone to normal or testosterone deficient women can help improve muscle mass and performance.

  Many of the above symptoms fall into the category of what is generally considered to be premenstrual syndrome (PMS). In general, women with premenstrual syndrome compared to controls have reported low levels of testosterone throughout the menstrual cycle. In the UK and Australia, testosterone supplementation is currently used as a treatment for premenstrual syndrome. Management of premenstrual syndrome with estradiol / testosterone implants resulted in improved libido, sex pleasure and fatigue. Thus, it is believed that the methods, kits, combinations and compositions of the present invention can be useful for treating premenstrual syndrome in women, particularly in combination with estrogen administration.

  In one embodiment of the invention, the methods, kits, combinations and compositions are useful for suppressing cellular and humoral immune responses in women. Androgens appear to suppress cellular and humoral immune responses. Many researchers have proposed increasing testosterone levels in women as protecting against autoimmune diseases such as rheumatoid arthritis. Testosterone administration is therefore considered effective in the treatment of women with such disorders.

The toxicity and therapeutic efficacy of the therapeutic agents of the present invention are standard pharmaceutical grades such as the measurement of LD ₅₀ (dose that is lethal to 50% of the population) and ED ₅₀ (dose that is therapeutically effective for 50% of the population). It can be measured by a technique. The dose ratio between toxic and therapeutic effects is the therapeutic index and may be expressed by the ratio LD 50 _/ ED _50. Compounds that exhibit large therapeutic indices are preferred. Although compounds that exhibit adverse side effects can be used, a delivery system designed to target sites of affected tissues to reduce side effects by minimizing the possibility of injury to uninfected cells Consideration must be made.

  The active agents of the present invention can be administered in the form of salts, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, derivatives and other forms as desired. , Such salts, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs, or derivatives are pharmacologically appropriate, ie, the method, kit To be effective in combinations and compositions. Salts, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives of active agents are known to those skilled in the art of synthetic organic chemistry, for example see J. Org. March, Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th edition (New York: Wiley-Interscience, 1992). For example, acid addition salts are prepared from the free base using conventional methods and involve reaction with a suitable acid. In general, the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added to it. The resulting salt precipitates or can be removed from the solution by the addition of a less polar solvent. Suitable acids for preparing acid addition salts include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid. Organic acids such as acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and others, as well as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. An inorganic acid is mentioned. Acid addition salts can be reconverted to the free base by treatment with a suitable base. Illustratively, the acid addition salts of activators herein include halogen salts as prepared using hydrochloric acid or hydrobromic acid. Illustratively, basic salts include alkali metal salts such as sodium and copper salts. Preparation of esters involves functionalization of hydroxyl and / or carboxyl groups that can be present in the molecular structure of the drug. Esters are generally acyl-substituted derivatives of free alcohol groups, ie moieties derived from carboxylic acids of the formula RCOOH, where R is alkyl, preferably lower alkyl. The ester can be reconverted to the free acid, if desired, using conventional hydrogenolysis or hydrolysis techniques. Amides and prodrugs can also be prepared using techniques known in the art or described in the relevant literature. For example, amides can be prepared from esters using appropriate amine reactants, or amides can be prepared from anhydrides or acid chlorides by reaction with ammonia or lower alkyl amines. Prodrugs are generally prepared by covalent attachment of certain moieties, resulting in compounds that are not therapeutically active until modified by the individual's metabolic system.

  The therapeutic agents of the invention can be formulated as a single pharmaceutical composition comprising at least one therapeutic agent or as multiple independent pharmaceutical compositions, each composition comprising at least one therapeutic agent. Pharmaceutical compositions according to the present invention include compositions having at least one therapeutic agent formulated for transdermal administration. Transdermal administration includes transdermal delivery systems including patches, gels, tapes and creams, which include alcohol, excipients such as permeation enhancers and thickeners, and solubilizers (eg, propylene glycol, bile salts). And amino acids), hydrophilic polymers (eg polycarbophil and polyvinylpyrrolidone) and adhesives, and tackifiers (eg polyisobutylene, silicone based adhesives, acrylates and polybutenes).

  The therapeutic agents of the invention can then be administered transdermally in dosage unit formulations, optionally containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The compounds of the present invention can be administered by any conventional means available in combination with pharmaceuticals, either as individual therapeutic compounds or as combinations of therapeutic compounds.

  The compositions of the present invention may be used to treat, prevent, or reduce the risk of developing testosterone deficiency in a mammal with a site of action in the mammal's body, such as the ileum, plasma, central nervous system or liver. Administration can be by any means of contact.

  Furthermore, the methods, kits, combinations and compositions of the present invention can optionally include salts, emollients, stabilizers, antimicrobial agents, fragrances and propellants.

  In other embodiments of the invention, the therapeutic agent is in the form of a kit or package comprising testosterone. Illustratively, a kit or package includes a testosterone in a dosage form, such as a gel or patch suitable for transdermal administration, in an amount for proper dosing of the drug. The therapeutic agents of the invention can be packaged in the form of a kit or package in which daily (or other periodic) dosages are prepared for appropriate sequential or simultaneous administration. The present invention further provides a kit or package comprising a plurality of dosage units adapted for daily administration, each dosage unit comprising at least one therapeutic agent of the invention. This drug delivery system can be used to facilitate administration of any of the various embodiments of the therapeutic composition. In one embodiment, the system includes multiple dosages administered daily or weekly through transdermal administration. The kit or package includes a set of instructions for the patient.

  The methods, kits, combinations and compositions may be used for other steroids such as progesterone, or agents that increase testosterone levels in mammals, such as agents that inhibit the synthesis of sex hormone binding globulin, or, as described above, estrogen It can also be used in “combination therapy” with like hormones.

  In other embodiments, these methods, kits, combinations and compositions are used in combination with other steroids or agents effective in treating, preventing or reducing the risk of developing testosterone deficiency disorders in a subject.

  Steroids or agents that increase mammalian testosterone levels useful in the methods, kits, combinations and compositions of the present invention include compounds that inhibit the synthesis of sex hormone binding globulin. Sex hormone-binding globulins are serum proteins that are known to bind testosterone and estradiol to affect the biological activity of these hormones. Compounds of particular interest that inhibit the synthesis of sex hormone binding globulin include, but are not limited to, methyltestosterone and fluoxymesterone, and all salts, esters, hydrates, amides, mirror images of these compounds There are isomers, isomers, tautomers, polymorphs, prodrugs or derivatives. Methyltestosterone is available today in a variety of formulations including those available for oral administration, such as ANDROID® and TESTRED®. Fluoxymesterone is also available today in a variety of formulations including those available for oral administration, such as HALOSTESTIN®. Combinations of the above compounds can be used.

  Without wishing to be bound by theory, methyltestosterone appears to reduce the synthesis by the liver of endogenous proteins such as sex hormone binding globulin. This decrease in synthesis results in a decrease in blood levels of sex hormone binding globulin, which is the primary means of endogenous hormone transport. The decrease in sex hormone binding globulin causes an increase in the concentration of free hormone that subsequently binds to the receptor. Transdermal administration of androgens, such as testosterone, or estrogens, such as estradiol, can provide a means of increasing hormone levels in the bloodstream because it avoids first-pass metabolism. Thus, when used in combination, methyltestosterone and transdermally administered testosterone (and optionally estradiol) provide a greater therapeutic effect and provide a means to increase hormone levels in the bloodstream. Methyltestosterone and testosterone (and optionally estradiol) are either entities alone, because reduced hormone binding capacity is associated with increased hormone bioavailability, resulting in higher free hormone concentrations produced by testosterone alone Produces a greater therapeutic effect.

  In another embodiment of the invention, the estrogenic hormone that can be used in combination with the methods, kits, combinations and compositions is the natural estrogen 17β-estradiol (β-estradiol; 1,3,5 (10) -estraditriene −3,17β-diol). Other estrogenic steroid hormones can be used with partial or complete replacement of 17β-estradiol, examples of which are biocompatible and effectively transdermally absorbed esters. Examples of estradiol esters include estradiol-3,17-diacetate; estradiol-3-acetate; estradiol-17-acetate; estradiol-3,17-divalerate; estradiol-3-valerate; estradiol-17-valerate; Mono, 17-mono and 3,17-dipropionate esters, corresponding cypionates, heptanoates, benzoates, other esters; ethinyl estradiol; estrone and other estrogenic steroids and salts thereof that can be administered by the transdermal route, It may be an enantiomer, isomer, tautomer, prodrug and derivative. Other estrogen-related compounds that can be used in the methods, kits, combinations and compositions of the present invention include, but are not limited to, conjugated estrogens (including estrone sulfate, echrin and 17-α-dihydroekiline), Estradiol valerate, estriol, estrone, estrone sulfate, estropipate, ethinyl estradiol, mestranol, and all salts, esters, hydrates, amides, enantiomers, isomers, tautomers of these compounds , Polymorphs, prodrugs or derivatives.

  Estrogenic hormones are available today in a variety of formulations, including, but not limited to, those that can be used as creams, pessaries, vaginal rings, vaginal tablets, transdermal formulations, gels, and oral tablets. Examples of vaginal creams are PREMARIN® (conjugated estrogens), ORTHO DIENOSTEROL® (dienosterols) and OBSTIN® (estriol). Available pessary formulations include ORTHO-GYNEST® (estriol) and TAMPOVAGAN® (stilbestrol). An example of a vaginal ring formulation is ESTRING® (estradiol) and an example of a vaginal tablet is VAGIFEM® (estradiol). Available transdermal estrogen formulations containing estradiol include ERC ALORA (R), CLIMARA (R), DERMESTRIL (R), ESTRADERM (R), ESTRADERM (R) TTS, ESTRADERM (R) There are MX, EVOREL (R), FEMATRIX (R), FEMPATCH (R), FEMSEVEN (R), MENOREST (R), PROGYNOVA (R) TS and VIVELLE (R). Estrogen gels containing estradiol include ESTROGEL (under development by the applicant) and SANDRENA®. Some estradiol can be used by being formulated as an implant pellet such as ESTRADIOL IMPLANT (registered trademark). Tablet formulations include PREMARIN® (conjugated estrogens), ESTRATAB® (estrogen esters), ESTRATEST® (estrogens esters, methyltestosterone), MENEST® (estrogens esters), CLIMAGEST ( (Registered trademark) (estradiol), CLIMAVAL (registered trademark) (estradiol), ELLESE SOLO (registered trademark) (estradiol), ESTRACE (registered trademark) (estradiol), PROGYNOVA (registered trademark) (estradiol), ZUMENON (registered trademark) ( Estradiol), HORMONIN® (estradiol, estrone, estriol), HARMOEN® (estrone), OGEN® (estropipate), and ORTHO-EST® (estropipate), and these All salts of compounds, Ether, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, and prodrugs or derivatives.

  Combinations of the estrogenic hormones described above can be used. In one embodiment of the invention, the serum concentration of estrogen increases to at least about 60 pg estrogen / ml serum within 24 hours of a single administration of a dosage unit of the invention comprising estrogen.

  In one embodiment, the estrogenic hormone is formulated in a hydroalcoholic gel for transdermal administration. The gel includes one or more lower alcohols, penetration enhancers, thickeners, and water. In addition, the estrogen gel optionally includes salts, relaxation agents, stabilizers, antibacterial substances, fragrances and propellants.

  Illustratively, an estrogen gel is composed of the approximate amounts of the following substances shown in Table 8 below.

  Those skilled in the art will appreciate that the components of this formulation can vary in amount and still remain within the spirit and scope of the present invention. For example, the composition can comprise about 0.1 to about 10 g estradiol, about 0.1 to about 5 g CARBOPOL, about 0.1 to about 5 g triethanolamine and about 30 to about 98 g ethanol.

  The term “combination therapy” is intended as part of a specific treatment plan aimed at providing the beneficial effects of the combined action of these therapeutic agents for the treatment of testosterone deficiency disorders in mammals. Of steroids in combination with other steroids or drugs that increase testosterone levels in mammals, or estrogenic hormones. The beneficial effects of the combination include, but are not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combined use of therapeutic agents. In general, co-administration of these therapeutic agents is performed over a period of time (usually minutes, hours, days, weeks, months or years depending on the combination selected). “Combination therapy” generally does not include the administration of two or more of these therapeutic agents as part of a separate monotherapy, concomitantly and arbitrarily combined in the present invention. “Combination therapy” includes sequential administration of these therapeutic agents, ie, administering each therapeutic agent at a different time, and administering these therapeutic agents, or at least two therapeutic agents substantially simultaneously. To do. Substantially simultaneous administration is accomplished, for example, by administering to the subject in a single gel with a fixed ratio of each therapeutic agent, or multiple, single agent capsules, tablets or gels for each therapeutic agent. can do. Sequential or substantially simultaneous administration of each therapeutic agent is any suitable, including but not limited to oral, transdermal, intravenous, intramuscular, and direct absorption through mucosal tissue. It can also be executed by a simple route. These therapeutic agents can be administered by the same route or by different routes. For example, the first therapeutic agent of the selected combination can be administered orally and the other therapeutic agent of the combination can be administered transdermally. Alternatively, for example, all therapeutic agents can be administered transdermally, or one of the therapeutic agents can be administered by direct absorption through intravenous, intramuscular, or mucosal tissue. The order in which the therapeutic agents are administered is not strictly critical. “Combination therapy” refers to, for example, other therapeutic agents such as, but not limited to, other bioactive ingredients such as agents that improve sexual ability, and non-drug therapies such as but not limited to the above therapeutic agents Can also be administered.

  Agents that improve sexual ability that can be used in conjunction with the methods, kits, combinations and compositions of the present invention include, for example, ArginMax ™; SureGasm ™; Vitara ™; Viacreme ™; Niagara (TM); Ultimate Libido (TM); X-cite (TM); Alprostadil; Bupropion (Wellutrin (TM) SR, Zyban (TM), Zyban (TM) LP, Quomen (TM), Zyntabac (TM) ); REC-2615 (Recordati); Phentolamine (Bimexes (TM), Zonagen (TM), Erxin (TM)) (GlaxoSmithKline, Zonagen); HMP-12 (HMP-1991012) (Molecular Design); LibiGel (TM)- E / T (Antares Pharma); nicotinic acid; 3-pyridinecarboxylic acid; androst-4-en-one, (17) -hydroxy- (17β); P2Y2 agonist; TA-179 (Tanabe Seiyaku); stearyl-norleucine -V P (SNV) (Senetek); NMI-870, NMI-921 (NitroMed); PT-141 (Palatin Technologies, US Pat. No. 6,051,555); Alprostadil (LAM Pharmaceutical) (US Pat. Nos. 6,224,573, 6306841, No. 5,942,545, 6046244); IPM tech (LAM Pharmaceutical); 981 (Ramot); Apomorphine HCI (Nastech, US Pat. No. 6,436,950); LGD-2226, LG-121071 (Ligand); Vardenafil (Bay-38-9456, Nuviva, Levitra (Bayer)); PT-14 (Palatin Technologies); flibanserin (Boehringer Ingelheim) (WO 94/24125); phentolamine mesylate (Vasomax (TM), Z-Max (TM), Vasofem (TM), Regitin (TM)) (Zonagen) (US Pat. No. 5,731,339); 7-day HRT transdermal (EMD-61409, Fem7 ™, FemSeven ™) (Merck); Iosatan + HCTZ (Pinzaar ™ plus, Hizaar ™, Lortann ™) ), Neo-Lotan ™) (Bristol-Meyer Squibb) (International Publication 94/09778); MS-325 (AngioMark ™, Vasovist ™), ZK-23 018) (EPIX Medical) (International Publication 06/23526); Tadalafil (Cialis ™, PDE-A, PDE-CV, GF-196960, IC-351) (Eli Lilly) (US Pat. No. 6,143,746, International Publication) 95/19978); atipomezole (Antisedan ™, MPV-1248) (Orion Pharama) (European Patent No. 183492); duloxetine HCl (Eli Lilly) (US Pat. No. 5,362,886); bupropion ( 323U66, amphetbutamon, BW-323U, Wellbutrin ™ (GlaxoSmithKline) (US Pat. No. 4,424,363; agents that cause vasodilation (see, eg, US Pat. Nos. 5,877,216, 6,506,765, 6,395,574 and 6294550) ); Provide nitric oxide An agent that provides, transmits or releases (see, eg, US Pat. No. 6,472,425); 5-HT1A receptor agonists (eg, VML-670, CEB-1555 (Eli Lilly)); production of endogenous endothelium-derived relaxing factor An agent that induces; an agent that stimulates the endogenous synthesis of nitric oxide; an agent that is a substrate for nitric oxide synthase; or a phosphodiesterase inhibitor (see, eg, US Pat. No. 6,469,016). .

  Examples of the vasodilator that can be used in combination with the methods, kits, combinations and compositions of the present invention include vasodilators, ergotamines, nitrovasodilators, ACE inhibitors, leukotriene inhibitors, angiotensin receptor antagonists, Phosphodiesterase inhibitors, direct vasodilators, adrenergic receptor antagonists, β2-adrenergic agonists, calcium channel blockers, α blockers, β blockers, sympathomimetics, vitamins, organic nitrates, serotonin receptor blockers , Angina blockers, antihypertensives, cardiac stimulants, kidney and vascular function improvers, sympathomimetic amines, natural prostaglandins (see eg US Pat. No. 6,036,977), synthetic prostaglandin derivatives, endothelium-derived relaxation Factor, Vasoactive Intestinal Polypeptide Agony , Smooth muscle relaxants, and a leukotriene inhibitor. Examples of vasodilators include apomorphine, apomorphine N-glucuronide, apomorphine O-glucuronide, apomorphine O-sulfate, apomorphine N-sulfate, norapomorphine, norapomorphine O-glucuronide, norapomorphine N-glucuronide, norapomorphine O -Sulfate, norapomorphine N-sulfate, niacin, nitroglycerin, hydrochloric acid, hydrochlorothiazide, nilatrin hydrochloride, pentoxyphylene, phenoxybenzamine, diclofenac, papaverine, hydralazine, sodium nitroprusside, hydrochloric acid Isoxaprine, epoprosturol sodium, nyridrin hydrochloride, torazoline hydrochloride, nicotinyl alcohol, nicotinic acid, nicotinic acid precursor, ni Ester of chic acid and phentolamine, phentolamine mesylate, phentolamine hydrochloride, yohimbine, timoxamine imipramine, verapamil, isoxsuprine, naphthidrofuryl, trazoline, hydroisosorbide, dibenamine, dinitrate, captopril, enalapril, enalaprilate, quinapril ramipril, lisinol Losartan, amrinone, milrinone, vesnarinone, nicorandil, prazosin, labetalol, seriprolol, carvedilol, bucindolol, nifedipine butamine, minoxidil, nitric acid and nilidrin, or salts, esters, hydrates, amides, enantiomers, isomerism , Tautomers, polymorphs, prodrugs or derivatives. Combinations of the aforementioned vasodilation inducers can be used.

  Illustratively, nitrates that can be used in conjunction with the methods, kits, combinations and compositions of the present invention include nitroglycerin, isosorbide nitrate, erythrityl nitrate, amyl nitrate, molsidomine, linsidomine chlorhydrate, S- Nitroso-N-acetyl-d, l-penicillamine and S-nitroso-N-glutathione; or salts, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or Derivatives. Combinations of the above nitric acid drugs can be used.

  Illustratively, alpha blockers that can be used in conjunction with the methods, kits, combinations and compositions of the present invention include phenoxybenzamine, dibenamine, doxazosin, terazosin, phentolamine, trazoline, prazosin, trimazosin, alfuzosin, tansulosin Ergot alkaloids such as ergotamine and ergotamine analogues, such as acetergamine, brazergoline, bromerguride, cyanergoline, delorgotrile, disulergine, disulergine, Ergonobine acid, ergotamine tartrate, etisulergine, lergotolyl, lysergide, meslergin, metergoline, metaergotamine, nicergoline, pe Golid, propisergide, proterguride and terguride; antihypertensive drugs such as diazoxide, hydralazine and minoxidil; nimodepine; pinacidil; cyclandelate; dipyridamole; isoxpurine; chlorpromazine; Or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug or derivative thereof; Combinations of the above alpha blockers can be used.

Illustratively, natural prostaglandins that can be used in conjunction with the methods, kits, combinations and compositions of the present invention include prostaglandin E ₀ , prostaglandin E ₁ , prostaglandin A ₁ , prostaglandin B. ₁ , prostaglandin F _1α , 19-hydroxy-prostaglandin A ₁ , 19-hydroxy prostaglandin B ₁ , prostaglandin E ₂ , prostaglandin A ₂ , prostaglandin B ₂ , 19-hydroxy-prosta There are glandin A ₂ , 19-hydroxy-prostaglandin B ₂ , prostaglandin E ₃ , prostaglandin F _3α and prostaglandin I ₂ . Examples of synthetic prostaglandins include carboprosttromethamine, dinoprosttromethamine, dinoprostone, lipoprost, gemeprost, metenoprost, sulprostone and tiaprost; or salts, esters, hydrates, amides, Enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives. Combinations of the above natural prostaglandins can be used.

  Examples of the endothelium-derived relaxing factor include sodium nitroprusside, diazeniumdiolate, (Z) -1- {N-methyl-N- [6- (N-methyl-ammoniohexyl) amino]} diazen-1- Ium-1,2-diolate, (Z) -1- [N- (3-ammoniopropyl) -N- (n-propyl) amino] diazen-1-ium-1,2-diolate, (Z)- 1- {N- [3-aminopropyl] -N- [4- (3-aminopropylammonio) butyl] amino} diazen-1-ium-1,2-diolate and sodium (Z) -1- (N , N-diethylamino) -diazen-1-ium-1,2-diolate; or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug or Derivatives. Combinations of the aforementioned endothelium-derived relaxing factors can be used.

  Suitable phosphodiesterase inhibitors that can be used in combination with the methods, kits, combinations and compositions of the present invention include, but are not limited to, type III phosphodiesterase (cAMP-specific cGMP inhibitory form), type IV phosphodiesterase (high affinity) High specificity cAMP form) and inhibitors of type V phosphodiesterase (cGMP specific form). Further inhibitors that can be used in conjunction with the present invention are cGMP-specific phosphodiesterase inhibitors other than type V inhibitors, including, for example, pyrazolopyrimidinone.

  Examples of type III phosphodiesterase inhibitors that can be used in conjunction with the methods, kits, combinations and compositions of the present invention include, but are not limited to, bipyridines such as milrinone and amirinone, piroximone and Imoxizolones such as enoximone, imazodan, dihydropyridazinones such as 5-methylimidazolane, indolidan and ICI1118233, quinolinone compounds such as cilostamide, cilostamide and besnarinone, and bemoradan (bemora) , Anergrelide, siguazodan, trequinsin, pimobendan, SKF-94120, SKF-95654, lixazinone and isomazo Other molecules such as isomazole, or salts, esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives thereof. Combinations of the type III phosphodiesterase inhibitors described above can be used.

  Examples of type IV phosphodiesterase inhibitors that can be used in combination with the methods, kits, combinations and compositions of the present invention include, but are not limited to, rolipram and rolipram derivatives such as RO20-1724, nitroaquazone and nitroaqua. Zone derivatives such as CP-77059 and RS-25344-00, xanthine derivatives such as denbufylline and ICI63197, and other compounds such as EMD54622, LAS-31025 and etazolate; or salts, esters, hydrates thereof; Product, amide, enantiomer, isomer, tautomer, polymorph, prodrug or derivative. Combinations of the type IV phosphodiesterase inhibitors described above can be used.

  Examples of type V phosphodiesterase inhibitors that can be used in combination with the methods, kits, combinations and compositions of the present invention include, but are not limited to, zaprinast, MY5445, TA-179, dipyridamole and sildenafil, or salts thereof, Examples include esters, hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives. Other type V phosphodiesterase inhibitors are disclosed in PCT publications WO 94/28902 and WO 96/16644. In one embodiment, inhibitors of phosphodiesterase type 5 (“PDE5”), such as VIAGRA® (sildenafil citrate USP) are used. Combinations of the above-described V-type phosphodiesterase inhibitors can be used.

  The phosphodiesterase inhibitors described in PCT publication WO 96/16644 include glyceolic acid derivatives, 2-phenylpurinone derivatives, phenylpyridone derivatives, fused and fused pyrimidines, pyrimidopyrimidine derivatives, There are purine compounds, quinazoline compounds, phenylpyrimidinone derivatives, imidoazoquinoxalinone derivatives or their aza analogs, phenylpyridone derivatives and others. Specific examples of the phosphodiesterase inhibitors disclosed in WO96 / 16644 include 1,3-dimethyl-5-benzylpyrazolo [4,3-d] pyrimidin-7-one, 2- (2-propoxyphenyl) ) -6-prinone, 6- (2-propoxyphenyl) -1,2-dihydro-2-oxypyridine-3-carboxamide, 2- (2-propoxyphenyl) -pyrido [2,3-d] pyrimido-4 (3H) -one, 7-methylthio-4-oxo-2- (2-propoxyphenyl) -3,4-dihydro-pyrimido [4,5-d] pyrimidine, 6-hydroxy-2- (2-propoxyphenyl) ) Pyrimidine-4-carboxamide, 1-ethyl-3-methylimidazo [1,5a] quinoxalin-4 (5H) -one, 4-phenylmethylamino-6 Chloro-2- (1-imidazoloyl) quinazoline, 5-ethyl-8- [3- (N-cyclohexyl-N-methylcarbamoyl) -propyloxy] -4,5-dihydro-4-oxo-pyrido [ 3,2-e] -pyrrolo [1,2-a] pyrazine, 5′-methyl-3 ′-(phenylmethyl) -spiro [cyclopentane-1,7 ′ (8′H)-(3′H) -Imidazo [2,1b] purine 4 '(5'H) -one, 1- [6-chloro-4- (3,4-methylenedioxybenzyl) -aminoquinazolin-2-yl) piperidine-4-carvone Acid, (6R, 9S) -2- (4-trifluoromethyl-phenyl) methyl-5-methyl-3,4,5,6a, 7,8,9,9a-octahydrocyclopent [4,5] -Midazo [2,1-b]- Purin-4-one, 1t-butyl-3-phenylmethyl-6- (4-pyridyl) pyrazolo [3,4-d] -pyrimido-4-one, 1-cyclopentyl-3-methyl-6- (4- Pyridyl) -4,5-dihydro-1H-pyrazolo [3,4-d] pyrimid-4-one, 2-butyl-1- (2-chlorobenzyl) 6-ethoxy-carbonylbenzimidazole, And 2- (4-carboxypiperidino) -4- (3,4-methylenedioxy-benzyl) amino-6-nitroquinazoline, and 2-phenyl-8-ethoxycycloheptimidazole; or salts and esters thereof Hydrates, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs or derivatives. Combinations of the above phosphodiesterase inhibitors can be used.

  Other V-type phosphodiesterase inhibitors useful in combination with the present invention include IC-351 (tadalafil (Cialis®)); 4-bromo-5- (pyridylmethylamino) -6- [3- (4 -Chlorophenyl) propoxy-]-3 (2H) pyridazinone; 1- [4-[(1,3-benzodioxol-5-ylmethyl) amiono] -6-chloro-2-quinazolinyl] -4-piperidine-carboxylic acid, monosodium salt; (+)-cis-5,6a, 7,9,9,9a-hexahydro-2- [4- (trifluoromethyl) -phenymmethyl-5- Methyl-cyclopent-4,5] imidazo [2,1-b] purine-4 (3H) one; furazlocillin; cis-2-hexyl-5-methyl-3,4,5,6 , 7,8,9,9a-octahydrocyclopent [4,5] imidazo [2,1-b] purin-4-one; 3-acetyl-1- (2-chlorobenzyl) -2-propylindole- 6-carboxylic acid; 4-bromo-5- (3-pyridylmethylamino) -6- (3- (4-chlorophenyl) propoxy) -3- (2H) pyridazinone; 1-methyl-5- (5-morpholinoacetyl 2-n-propoxyphenyl) -3-n-propyl-1,6-dihydro-7H-pyrazolo (4,3-d) pyrimidin-7-one; 1- [4-[(1,3-benzodio Xol-5-ylmethyl) amino] -6-chloro-2-quinazolinyl] -4-piperidinecarboxylic acid, monosodium salt; Pharmaprojects No. 4516 (Glaxo Wellcome); Pharmaprojects No. 5051 (Bayer); Pharmaprojects No. .5064 Kyowa Hakko; see WO 96/26940); Pharmaprojects No. 5069 (Schering Plow); GF-196960 (Glaxo Wellcome); and Sch-51866; or its salts, esters, hydrates, amides, enantiomers , Isomers, tautomers, polymorphs, prodrugs or derivatives. Combinations of the type IV phosphodiesterase inhibitors described above can be used.

  The compounds described in PCT publication WO 94/28902 are pyrazolopyrimidinones. Examples of these inhibitory compounds include 5- (2-ethoxy-5-morpholinoacetylphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidine. -7-one, 5- (5-morpholinoacetyl-2-n-propoxyphenyl) -1-methyl-3-n-propyl-1,6-dihydro-7-H-pyrazolo [4,3-d] pyrimidine -7-one, 5- [2-ethoxy-5- (4-methyl-1-piperazinylsulfonyl) -phenyl] 1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4 , 3-d] pyrimidin-7-one, 5- [2-allyloxy-5- (4-methyl-1-piperazinylsulfonyl) -phenyl] -1-methyl-3-n-propyl-1,6- Dihydro-7H-pyrazolo 4,3-d] pyrimidin-7-one, 5- [2-ethoxy-5- [4- (2-propyl) -1-piperazinylsulfonyl) -phenyl] -1-methyl-3-n-propyl -1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [2-ethoxy-5- [4- (2-hydroxyethyl) -1-piperazinylsulfonyl) phenyl ] -1-Methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5- [5- [4- (2-hydroxyethyl) -1 -Piperazinylsulfonyl] -2-n-propoxyphenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, 5 [2 -Ethoxy-5- (4-methyl-1-piperazi Rucarbonyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one, and 5- [2-ethoxy-5- (1) -Methyl-2-imidazolyl) phenyl] -1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo [4,3-d] pyrimidin-7-one; or its salts, esters, hydration Product, amide, enantiomer, isomer, tautomer, polymorph, prodrug or derivative. Combinations of the above-described pyrazolopyrimidinones can be used.

  Other phosphodiesterase inhibitors that can be used in the methods of the invention include nonspecific phosphodiesterase inhibitors such as theophylline, IBMX, pentoxifylline and papaverine, and direct vasodilators such as hydralazine.

  Combinations of agents that improve sexual ability as described above can be used in the methods, kits, combinations and compositions herein.

  The therapeutic compounds making up the combination therapy can be in a combined dosage form or in separate dosage forms intended for substantially simultaneous transdermal administration. The therapeutic compounds that make up the combination therapy can also be administered sequentially, with any therapeutic compound being administered in a regimen that requires two-step administration. Thus, certain regimens may require sequential administration of therapeutic compounds by administering separate active agents at intervals. The time period between multiple administration phases depends on the effects of food intake and the age, condition of the patient, and includes the efficacy, solubility, bioavailability, plasma half-life and kinetic profile of the therapeutic compound Depending on the properties of each therapeutic compound, it may be from a few minutes to several hours. Circadian variation of the target molecule concentration may also determine the optimal dosing interval. Regardless of whether they are administered simultaneously, substantially simultaneously, or sequentially, the therapeutic compound of the combination therapy includes administration of one therapeutic compound by the oral route and administration of the other therapeutic compound by the transdermal route. You can include the required prescription plan. The therapeutic compound of the combination therapy is injected orally, by inhalation spray, rectally, topically, buccally (eg sublingually) or parenterally (eg subcutaneously, intramuscularly, intravenously and intradermally). Or each infusion technique), whether administered separately or together, each such therapeutic compound is in a suitable pharmaceutical formulation of a pharmaceutically acceptable excipient, diluent or other formulation component. included. Examples of suitable pharmaceutically acceptable formulations containing therapeutic compounds are given above. In addition, pharmaceutical formulations are discussed, for example, in Hoover, John E., Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania, 1975. Other discussions of drug formulations can be found in Liberman, H.A. and Lachman, L. Ed., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980.

  In one embodiment of the invention, a method for identifying a subject having a testosterone deficiency disorder, or a subject at risk of developing it, is determined by the serum level of testosterone (or any other hormone) in the subject, which is a simple blood test. Can be achieved. For example, a subject's blood is evaluated for hormone concentrations and their levels are compared to optimal or predetermined physiological levels. In one embodiment, the target serum level concentration of free testosterone is about 0.1 pg to about 10 μg / ml serum, the target serum level concentration of progesterone is about 0.25 μg to about 75 μg / ml serum, and / or The target serum level concentration of estrogen is about 1 μg to about 1000 μg / ml serum. In other embodiments of the invention, the target serum level concentration of free testosterone is about 3 pg / ml serum, the target serum level concentration of progesterone is about 10 μg to about 25 μg / ml serum, and / or the target serum level of estrogen The level concentration is about 100 μg to about 200 μg / ml serum. Other risk factors described above can also be used to identify subjects with testosterone deficiency disorder or subjects who are at risk of developing the disease.

  Based on the comparison of the patient's hormone level to a target or predetermined physiological level, a dosing schedule is established for the patient to replenish the missing hormone level to the target physiological level. After initial evaluation and establishment of a prescription plan, monitor the patient by similar blood tests every 7-30 days until the patient reaches a target or predetermined physiological level and adjust the dosage of hormone administration accordingly It is also contemplated to do. Once the target level is established, the prescription plan indicates that the patient will follow the established dosage of the replacement hormone indefinitely in order to maintain the target or predetermined physiological level. Periodic blood tests are then performed to confirm that the target or predetermined physiological level is maintained.

In one embodiment of the present invention, a pharmaceutical composition comprising testosterone in a hydroalcoholic gel dosage form is applied to an adult female premenopausal human subject having a subnormal free testosterone plasma concentration of about 0.4 mg to about 0.5 mg of testosterone. When administered transdermally at a dosage, (i) about 39 ng or more total testosterone C _max per 1 dL serum; (ii) about 19 ng or more total testosterone C _min per 1 dL serum; (iii) about 30 ng or more per 1 dL serum per or (vi) 1 dL serum; (iv) 1 dL serum per about 2.6ng more free testosterone _C max;; (v) 1dL serum per about 1.4ng more free testosterone _{C min C} avg of total testosterone _{C avg} of about 2.1ng more free testosterone, at least One shows the 24-hour testosterone pharmacokinetic profile having the dosages are administered from one of a plurality of dosage unit form. In another embodiment, the testosterone composition is administered for 7 consecutive days, and on day 7, the following items (i) about 89 ng or more of total testosterone C _max per 1 dL serum; (ii) about 62 ng or more per 1 dL serum (iii) 1 dL serum per about 76ng more total testosterone _C avg;; (iv) 1dL serum per about 6.5ng more free testosterone _C max; (v) 1dL serum dose of about 5 _C min of total testosterone. 24 shows a 24-hour testosterone pharmacokinetic profile having at least one C _min of 1 ng or more of free testosterone; or (vi) C _avg of about 5.6 ng or more of free testosterone per 1 dL serum.

In another embodiment of the present invention, a pharmaceutical composition comprising testosterone in a hydroalcoholic gel dosage form is administered to an adult female premenopausal human subject having a subnormal free testosterone plasma concentration for about item (i) 1 dL serum: C _max of 52 ng or more of total testosterone; (ii) C _min of about 18 ng or more of total testosterone per 1 dL serum; (iii) C _avg of about 35 ng or more of total testosterone per 1 dL serum; (iv) about 5 per 1 dL serum. At least one of C _max of 5 ng or more of free testosterone; (v) C _min of about 1.8 ng or more of free testosterone per 1 dL serum; or (vi) C _avg of about 3.5 ng or more of free testosterone per 1 dL serum. 24 hour testosterone pharmacokinetic profile with Transdermally administered at a dose sufficient to Las, dosage is administered from one of a plurality of dosage unit form. In another embodiment, the testosterone composition is administered for 7 consecutive days, and on day 7, the following items (i) C _max of about 88 ng or more of total testosterone per 1 dL serum; (ii) about 43 ng or more per 1 dL serum _C of total testosterone of at least about 66ng per (iii) 1 dL serum avg;; _C in free testosterone of more than about 7.8ng per (iv) 1 dL serum max; (v) 1dL serum dose of about 3 _C min of total testosterone. 24 shows a 24-hour testosterone pharmacokinetic profile having at least one C _min of 5 ng or more of free testosterone; or (vi) C _avg of about 5.6 ng or more of free testosterone per 1 dL serum. In one embodiment, the hydroalcoholic gel dose administers about 0.8 mg to about 0.9 mg of testosterone to the subject.

In one embodiment of the present invention, a pharmaceutical composition comprising testosterone in a hydroalcoholic gel dosage form is administered to an adult female menopausal human subject having a subnormal free testosterone plasma concentration of about 19 ng or more per 1 dL serum: (ii) 1 dL serum per about 8ng more total testosterone _C min;; (iii) 1dL serum per about 14ng more total testosterone _C avg; (iv) 1dL serum per about 5.5ng more _C max of total testosterone At least one of: C _max of free testosterone; (v) C _min of about 1.8 ng or more of free testosterone per 1 dL serum; or (vi) C _avg of about 3.5 ng or more of free testosterone per 1 dL serum. Provides a 24-hour testosterone pharmacokinetic profile Administered in doses sufficient, the dosage is administered from one of a plurality of dosage unit form. In another embodiment, the testosterone composition is administered for 7 consecutive days, and on day 7, the following item (i) a C _max of about 44 ng or more of total testosterone per 1 dL serum; (ii) about 21 ng or more per 1 dL serum _C of total testosterone of at least about 32ng per (iii) 1 dL serum avg;; _C in free testosterone of more than about 7.8ng per (iv) 1 dL serum max; (v) 1dL serum dose of about 3 _C min of total testosterone. 24 shows a 24-hour testosterone pharmacokinetic profile having at least one C _min of 5 ng or more of free testosterone; or (vi) C _avg of about 5.6 ng or more of free testosterone per 1 dL serum. In one embodiment, the hydroalcoholic gel dose administers about 0.4 mg to about 0.5 mg of testosterone to the subject.

In another embodiment of the present invention, a pharmaceutical composition comprising testosterone in a hydroalcoholic gel dosage form is administered transdermally to an adult female premenopausal human subject having a subnormal free testosterone plasma concentration, wherein: C _max of about 61 ng or more total testosterone per 1 dL serum; (ii) C _min of about 10 ng or more total testosterone per 1 dL serum; (iii) C _avg of about 34 ng or more total testosterone per 1 dL serum; (iv) 1 dL serum C _max of about 2.6 ng or more of free testosterone per one; (v) C _min of about 0.8 ng or more of free testosterone per 1 dL serum; or (vi) C _avg of about 1.7 ng or more of free testosterone per 1 dL serum; 24 hour testosterone pharmacokinetics with at least one of Indicates Iru, dosages are administered from one of a plurality of dosage unit form. In another embodiment, the testosterone composition is administered for 7 consecutive days, and on day 7, the following item (i) C _max of about 106 ng or more of total testosterone per 1 dL serum; (ii) about 40 ng or more per 1 dL serum _C avg of total testosterone of at least about 64ng per (iii) 1 dL serum;; (iv) 1dL serum per about 5.6ng more free testosterone _C max; (v) 1dL serum dose of about 2 _C min of total testosterone. 24 shows a 24-hour testosterone pharmacokinetic profile having at least one C _{min of 3} ng or more of free testosterone; or (vi) C _avg of about 3.4 ng or more of free testosterone per 1 dL serum. In one embodiment, the composition comprises about 0.1% to about 10% testosterone, or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug thereof Or a derivative, an alcohol selected from the group consisting of about 30% to about 98% ethanol or isopropanol, about 0.1% to about 5% isopropyl myristate, and about 0.1% to about 10%. 0.1N sodium hydroxide and about 0.1% to about 5% gelling agent, these percentages being by weight of the composition, the total of the components of the composition being about 100% by weight is there. In one embodiment, the hydroalcoholic gel dose administers about 0.8 mg to about 0.9 mg of testosterone to the subject.

  In yet another embodiment of the invention, the composition comprises about 1% testosterone, or a salt, ester, hydrate, amide, enantiomer, isomer, tautomer, polymorph, prodrug or derivative thereof. About 0.8% to about 1% polyacrylic acid, about 0.5% isopropyl myristate, about 4% to about 5% 0.1 N sodium hydroxide, about 72% to about 73 % Ethanol (95% (v / v)).

  In yet another embodiment, the amount of composition administered to a subject is a 0.44 g dose, delivering about 4.4 mg of testosterone to the skin.

  In yet another embodiment, the amount of composition administered to the subject is a 0.88 g dose, delivering about 8.8 mg of testosterone to the skin.

  In one embodiment, a method for treating a condition or disorder for which treatment with testosterone is indicated comprises transdermally administering the composition of the invention to a subject in need of such treatment. Such pathologies or disorders include, for example, hypogonadism, sexual dysfunction, decreased libido, hypercholesterolemia, abnormal electrocardiogram, vasomotor symptoms, diabetic retinopathy, hyperglycemia, hyperinsulinemia Disease, hypoinsulinemia, increased body fat percentage, hypertension, obesity, osteoporosis, osteopenia, vaginal dryness, vaginal wall thinning, climacteric symptoms and hot flashes, cognitive impairment, cardiovascular disease, central nervous system disorder, Alzheimer Disease, dementia, cataract, cervical cancer, uterine cancer, breast cancer, depression, improper embryo implantation in the uterus, premature ovarian failure and premature menopause.

  In another embodiment of the invention, the method for treating, preventing, or reducing the risk of developing testosterone deficiency disorder in an adult subject in need thereof comprises (i) from less than about 0.2 ng per 1 dL serum. Identifying an adult female premenopausal human subject having a free testosterone plasma concentration of about 0.5 ng per 1 dL serum; and (ii) administering an amount of the composition of claim 1 to the area of the subject's skin; Wherein the amount delivers a therapeutically effective amount of testosterone to the serum of the subject, thereby reducing the risk of developing testosterone deficiency disorder or testosterone deficiency disorder.

  The invention is further illustrated by the following examples, which should not be construed as limiting in any way. In the following examples, it is assumed that women with a normal cycle produce about 300 μg of testosterone per day, and their serum testosterone levels generally range from about 20 ng / dL to about 80 ng / dL, on average About 40 ng / dL. Bilateral oophorectomy in premenopausal women reduces testosterone production by about 50%, resulting in an average total serum level of about 20 ng / dL. From a physiological point of view, testosterone therapy in women who became menopausal, for example, due to surgery experiencing female sexual dysfunction, supplemented about 150 μg of lost ovarian testosterone production per day to testosterone and its active androgen metabolism The level of the product dihydrotestosterone (DHT) is restored to their previous level within the normal physiological range.

(Example)
The following examples are provided to illustrate the invention and are not intended to be limiting in any way. Unless otherwise stated, in these examples, testosterone is formulated as a gel for transdermal administration as previously described in Table 4.

Increased Testosterone Concentration in Premenopausal Women with Subnormal Testosterone Concentration After Administration of 4.4 mg Testosterone in a 1% Gel Formulation This example is for premenopausal women with subnormal free testosterone concentrations. FIG. 5 shows an increase in serum testosterone levels after administration of 4 mg transdermal testosterone as a 1% aqueous alcohol gel.

  In this example, five premenopausal women aged 18 to 65 were enrolled in the study. Subjects were identified as having free (unbound) testosterone concentrations below normal at that age, with free (unbound) testosterone concentrations at screening ranging from 0.2 to 0.5 ng / dL. Furthermore, subjects were unable to receive testosterone therapy, become pregnant or lactating, diabetic, or receive any antidepressant therapy within 30 days of screening.

  The woman was administered 0.44 g of 1% testosterone gel formulation once a day at about 8:00 am for 7 days. The gel was dispensed from the glass bottle using a metered pump. The amount of testosterone in the administered daily dose was 4.4 mg. The gel was evenly applied simultaneously to the outer upper thigh and the skin of the waist on each day of the 7th test day.

  To measure testosterone pharmacokinetics, serial blood samples were obtained on Day 0 (Baseline), Day 1, and Day 7 of treatment. Serum collected from patients is not bound to either total (bound + unbound) testosterone or unbound testosterone (albumin and sex hormone binding globulin (SHBG)) using a validated sensitive specific radioimmunoassay ) Was analyzed.

The peak concentration (C _max ) during the dosing period and the lowest concentration (C _min ) during the dosing period were determined by examination. The mean concentration (C _avg ) during the dosing period was calculated as AUC _{(0-24) / 24} , where AUC _(0-24) is the concentration-time curve of the 24-hour dosing period determined using the trapezoidal formula. It was the lower area. If the assay results were missing, the AUC was calculated by extending the trapezoid to the next sample time. If the missing assay results are at day 0 or day 7 at the beginning or end of the dosing period, the missing value is 24 hours before assuming the patient was in steady state. Or estimated to be equivalent to the results of the assay after 24 hours.

  Topically administered testosterone-containing hydroalcoholic gels increased serum testosterone levels in premenopausal women with subnormal testosterone levels immediately after administration. Serum concentrations of total and free testosterone almost doubled by the end of the first day of treatment. A once-daily treatment for a total of 7 days resulted in a serum concentration of 3 to 6 times the pre-treatment level. Total testosterone levels (ng / dL) are shown in FIG.

Day 1 and Day 7 highest (C _max ), lowest (C _min ) and average (C _avg ) increase in total testosterone concentration, the highest (C _max ) at baseline (before starting treatment), Table 9 summarizes the minimum (C _min ) and average (C _avg ) total testosterone concentrations.

Baseline values for total testosterone mean concentration C _avg for 24 hours are shown in FIG. Baseline values ranged from 9 to 26 ng / mL, with an average value of 16 ng / mL.

On day 1 of treatment with 4.4 mg testosterone gel, the female total testosterone C _avg increased by 37-155% compared to baseline, with an average increase of 94%.

The values on day 7 of the total testosterone average concentration C _avg for 24 hours are shown in FIG. Administration of 4.4 mg testosterone gel resulted in a mean change from 16 ng / dL to 76 ng / dL in premenopausal women.

  Baseline concentrations of total testosterone showed slight diurnal variation and peak concentrations were associated with early morning samples in 5 subjects. Testosterone administration altered this diurnal pattern. With the administration of testosterone gel in the early morning (approximately the time when the normal highest testosterone concentration occurs), the highest serum concentration was observed at another time other than early morning in 4 out of 5 subjects. Thus, if a patient administers testosterone gel at night before going to bed, the timing and extent of the patient's diurnal variation will likely follow a normal pattern.

Studies to see if steady-state testosterone concentrations are predicted by day 1 marker concentrations, concentrations at each sample time on day 1 and C _avg on day 7 or days 0 and 7 A correlation was sought between changes in C _avg . The highest correlation was confirmed between 24-hour samples of C _{avg on} day 1 and day 7 (R ² = 0.35). This relationship indicates that the steady state C _avg on day 7 is approximately 23 ng / dL higher than the testosterone serum concentration measured 24 hours after administration of the first dose, i.e. just before the second administration of the gel. It can be predicted that.

As shown in FIG. 4, the serum concentration of free testosterone increased in parallel with the total testosterone concentration. Day 1 and Day 7 highest (C _max ), lowest (C _min ) and average (C _avg ) increases in free testosterone concentration, the highest (C _max ) at baseline (before starting treatment), Table 10 summarizes the minimum (C _min ) and average (C _avg ) free testosterone concentrations.

The mean change in free testosterone on treatment day 1 compared to baseline was 92%. On day 7, the mean C _{avg of} free testosterone was more than 2 times to about 5 times the pre-treatment level, and one patient showed a 10-fold increase in free testosterone on day 7. Administration of 4.4 mg testosterone gel increased the mean C _avg of free testosterone to 5.6 ng / dL in premenopausal subjects.

1 and 7 days of up to _{(C max),} minimum _{(C min)} and maximum _{(C max)} of the mean free fraction of testosterone _{(C avg),} at baseline (before starting treatment), Table 11 summarizes the lowest (C _min ) and average (C _avg ) testosterone free fractions.

As shown in Table 11, in premenopausal women administered 4.4 mg of testosterone, the average free fraction average changed from 6.3% to 7.4%, and the average change from day 0 to day 7 is It was an increase of 1.1%. C _avg of free fraction at baseline varied from 2.1% to 11% in 5 subjects. The C _avg of the free fraction on the 7th day showed a similar fluctuation, and the value fluctuated from 1.8% to 11.3%.

Increased testosterone levels in premenopausal women with subnormal testosterone concentrations after administration of 8.8 mg testosterone in a 1% aqueous alcohol gel formulation. This example is for premenopausal women with subnormal free testosterone concentrations. FIG. 5 shows an increase in serum testosterone levels after administration of 8.8 mg of transdermal testosterone as a 1% aqueous alcohol gel.

  In this example, as before, five premenopausal women aged 18 to 65 were enrolled in the study. Women were administered 0.88 g of a 1% testosterone gel formulation (containing 8.8 mg testosterone) once a day for 7 days. Except for the amount of testosterone administered to the subject, all aspects of the study were identical to those described in Example 1.

  Topical administration of hydroalcoholic gels containing 8.8 mg of testosterone increased serum testosterone levels in premenopausal women with subnormal testosterone levels. The serum concentration of total and free testosterone almost doubled by the end of the first day of treatment. A total of 7 days of once-daily treatment resulted in a serum concentration of 2 to 7 times the pre-treatment level. Total testosterone levels (ng / dL) are shown in FIG.

Day 1 and Day 7 highest (C _max ), lowest (C _min ) and average (C _avg ) increase in total testosterone concentration, the highest (C _max ) at baseline (before starting treatment), Table 12 summarizes the minimum (C _min ) and average (C _avg ) total testosterone concentrations.

Baseline values for total testosterone mean concentration C _avg for 24 hours are shown in FIG. Baseline values ranged from 5 to 30 ng / mL, with an average value of 18 ng / mL.

On the first day of treatment with testosterone gel 8.8 mg, _{C avg} of testosterone compared to baseline increased from 38 to 220%, the average an increase of 9%.

The values on day 7 of the total testosterone average concentration C _avg for 24 hours are shown in FIG. Administration of 8.8 mg testosterone gel resulted in a mean change from 18 ng / dL to 66 ng / dL in the subjects.

  Baseline concentrations of total testosterone showed slight diurnal variation, and peak concentrations were associated with early morning samples in 1 out of 5 subjects. Testosterone administration altered the subject's diurnal pattern.

Similar to Example 1, the serum concentration of free testosterone increased in parallel with the total testosterone concentration. (FIG. 4). The highest (C _max ), lowest (C _min ) and average (C _avg ) increases in free testosterone concentrations on day 1 and day 7 at baseline (C _max ), lowest (C _min ) and average Table 13 summarizes the free testosterone concentration of (C _avg ).

The increase in mean free testosterone C _{avg on} the first day of treatment compared to baseline was 110%. On day 7, free testosterone C _avg was approximately 2 to 8 times the pre-treatment level. Administration of 8.8 mg testosterone gel increased C _avg of free testosterone from 1.7 ng / dL to 5.6 ng / dL in the subject on day 7.

The highest (C _max ), lowest (C _min ) and average (C _avg ) testosterone free fractions at day 1 and day 7 after administration of 8.8 mg testosterone to premenopausal women were measured at baseline. Table 14 summarizes the highest ( _Cmax ), lowest ( _Cmin ) and average ( _Cavg ) free fractions of testosterone.

  As shown in Table 14, in premenopausal women who received 8.8 mg of testosterone, the mean free fraction average changed from 9.9% to 9.6%, and the average change from day 0 to day 7 Was an increase of 1.1%. Baseline free fractions varied from 4.7% to 17.5% in 5 subjects. The free fraction on day 7 showed similar fluctuations, with values varying from 1.8% to 11.3%.

Increased free testosterone concentration in postmenopausal women with subnormal free testosterone concentration after administration of 4.4 mg testosterone in a 1% aqueous alcohol gel formulation This example is for postmenopausal women with subnormal free testosterone concentration Shows an increase in serum testosterone levels after administration of 4.4 mg of transdermal testosterone as a 1% aqueous alcohol gel.

  In this example, four postmenopausal women aged 18 to 65 were enrolled in the study. Subjects were identified as having free (unbound) testosterone concentrations below normal at that age, with free (unbound) testosterone concentrations at screening ranging from 0.2 to 0.5 ng / dL. Women were administered 0.44 g of 1% testosterone gel formulation (containing 4.4 mg of testosterone) once a day for 7 days. All aspects of the study were identical to those described in Example 1.

  As shown in FIG. 5, topical administration of an hydroalcoholic gel containing 4.4 mg of testosterone increased serum testosterone levels in postmenopausal women with subnormal testosterone levels immediately after administration. Serum levels of total and free testosterone had increased approximately 1.5 to 2 times by the end of the first day of treatment. A once-daily treatment for a total of 7 days resulted in a serum concentration of 2 to 5 times the pre-treatment level.

Increases in total (C _max ), minimum (C _min ), and average (C _avg ) total testosterone concentrations on day 1 and day 7 at baseline (C _max ), minimum (C _min ), and average Table 15 summarizes the total testosterone concentration of (C _avg ).

Baseline values for total testosterone mean concentration C _avg for 24 hours are shown in FIG. Baseline values for total testosterone C _avg were 6-18 ng / mL, with an average value of 11 ng / mL.

On the first day of treatment with testosterone gel 4.4 mg, _{C avg} of testosterone compared to baseline increased from 50 to 83%, on average an increase of 61%.

The values on day 7 of the total testosterone average concentration C _avg for 24 hours are shown in FIG. The level on day 7 was 2 to 4.5 times the pre-treatment level, and the mean change in total testosterone average concentration in the subjects ranged from 11 ng / dL to 32 ng / dL.

  Baseline concentrations of total testosterone show slight diurnal variation, with peak concentrations associated with early morning samples in all subjects, and administration of testosterone gel in the early morning (approximately the time when the normal highest testosterone concentration occurs) Even the highest serum concentrations were observed at different times other than early morning.

As shown in FIG. 6, the serum concentration of free testosterone increased with total testosterone concentration after 4.4 mg testosterone gel was administered to postmenopausal women. Day 1 and Day 7 highest (C _max ), lowest (C _min ) and average (C _avg ) increases in free testosterone concentration, the highest (C _max ) at baseline (before starting treatment), Table 16 summarizes the minimum (C _min ) and average (C _avg ) free testosterone concentrations.

Mean C _{avg for} free testosterone increased from 0.4 ng / dL at baseline to 3.5 ng / dL on treatment day 1 and 5.6 ng / dL on treatment day 7. On day 7, the average C _{avg of} free testosterone was more than 2 to 5 times the pre-treatment level.

1 and 7 days of up to _{(C max),} minimum _{(C min)} and maximum _{(C max)} of the mean free fraction of testosterone _{(C avg),} at baseline (before starting treatment), Table 17 summarizes the lowest (C _min ) and average (C _avg ) free fractions of testosterone.

  As illustrated in Table 17, the average free fraction changed from 4.1% to 4.7% in postmenopausal women receiving 4.4 mg of testosterone.

Increased testosterone levels in postmenopausal women with subnormal testosterone concentrations after administration of 8.8 mg testosterone in a 1% aqueous alcohol gel formulation. This example is for postmenopausal women with subnormal free testosterone concentrations. FIG. 5 shows an increase in serum testosterone levels after administration of 8.8 mg of transdermal testosterone as a 1% aqueous alcohol gel.

  In this example, as above, two postmenopausal women aged 18 to 65 were enrolled in the study. Women were administered 0.88 g of a 1% testosterone gel formulation (containing 8.8 mg testosterone) once a day for 7 days. The study method was the same as that described in Example 1.

  As shown in FIG. 5, topical administration of an aqueous alcohol gel containing 8.8 mg of testosterone increased serum testosterone levels in postmenopausal women with subnormal testosterone levels immediately after administration. Total testosterone and free testosterone concentrations increased significantly after 7 days of administration compared to baseline concentrations. Serum concentrations after 7 days of treatment with testosterone gel increased more than twice the baseline concentration in the first subject and more than 12 times the baseline concentration in the second subject.

Maximum (C _max ), minimum (C _min ) and average (C _avg ) total testosterone concentration values on day 1 and day 7, and baseline maximum (C _max ), minimum (C _min ) and average The total testosterone concentration values for (C _avg ) are summarized in Table 18.

Baseline values for total testosterone mean concentration C _avg for 24 hours are shown in FIG. Baseline C _avg total testosterone values were 7 ng / dL for the first subject and 16 ng / dL for the second subject. On the first day of treatment with 8.8 mg testosterone gel, C _avg values increased to 49 ng / dL in the first subject and 19 ng / dL in the second subject. On the seventh day of treatment, total testosterone C _avg values were 89 ng / dL and 38 ng / dL for the first and second subjects, respectively. Day 7 values of total testosterone C _avg are illustrated in FIG.

  Baseline concentrations of total testosterone showed slight diurnal variation, with peak concentrations associated with early morning samples in one subject. Testosterone administration changed the diurnal pattern of testosterone levels in subjects.

As shown in FIG. 6, the serum concentration of free testosterone increased in parallel with the total testosterone concentration. At baseline, the highest (C _max ), lowest (C _min ) and average (C _avg ) free testosterone concentrations on days 1 and 7 are summarized in Table 19.

At baseline, the mean C _{avg of} free testosterone was 0.4 ng / dL for the first subject and 1.2 ng / dL for the second subject. On day 1, the average C _avg increased to 2.0 ng / dL in the first subject, to 1.4 ng / dL in the second subject, and on day 7, the average C _{avg of} free testosterone was the first subject Was 4.0 ng / dL for the second subject and 2.8 ng / dL for the second subject.

Table 20 summarizes the highest (C _max ), lowest (C _min ) and average (C _avg ) testosterone free fractions at day 1 and day 7 at baseline.

  As shown in Table 20, in postmenopausal women receiving 8.8 mg testosterone, the mean free fraction averaged in the first subject from 6.3% at baseline to 4.7 on day 1 of treatment. % And 4.4% on the seventh day of treatment. In the second subject, the mean free fraction average varied from 7.9% at baseline to 7.4% on days 1 and 7 of treatment.

Effect of exogenous testosterone administration on menopausal status and serum testosterone levels This example shows pre-menopausal and post-menopausal after administration of 4.4 mg or 8.8 mg of transdermal testosterone as a 1% hydroalcoholic gel. Shows the effect of exogenous testosterone administration on serum testosterone levels in Japanese women. The study was performed as described in Examples 1-4.

  The results of this study are detailed in FIG. FIG. 7 shows that the extent to which exogenous testosterone increased serum testosterone levels was higher in premenopausal women than in postmenopausal women. The greatest increase in serum testosterone levels was observed in premenopausal women who received low doses of testosterone. Five of six postmenopausal women showed an increase in serum testosterone of less than 50 ng / dL, but only 50% of premenopausal women fell into that category. Premenopausal women did not show a dose dependency with respect to the degree of increase observed. The number of postmenopausal women who were administered higher doses was too low to confirm the presence of dose dependence in postmenopausal women.

3. Testosterone concentrations in postmenopausal women after administration of testosterone in a 1% aqueous alcohol gel formulation with or without hormone replacement therapy. This example is used with or without hormone replacement therapy. FIG. 5 shows increased serum testosterone levels in postmenopausal women after administration of 4 mg or 8.8 mg or 13.2 mg transdermal testosterone as a 1% aqueous alcohol gel.

  In this example, 24 postmenopausal women 51 years of age and older were enrolled in the study. Menopause was defined as multi-year menopause and / or FSH levels above 30 U / L in women not receiving estrogen replacement therapy. Participants had to have a serum testosterone level (early morning) of less than 33 ng / dL and normal PAP smears and mammograms for the previous 12 months. Subjects were divided into two groups. Group I includes 13 healthy postmenopausal women who have not been on hormone replacement therapy for at least 3 months, and Group II is 13 patients who have been treated for stable hormone replacement therapy for at least 3 months earlier Including postmenopausal women. Women who had undergone ovariectomy were not eligible to participate in the study.

  The study consisted of a screening period, a 24-hour baseline sampling period and a 5-week treatment period, where subjects were 1% testosterone hydroalcohol gel (Relibra®, Unimed Pharmaceuticals, Inc., Marietta, GA) daily. 4.4 mg, 8.8 mg or 13.2 mg was administered.

Serum total testosterone levels were measured using a radioimmunoassay using iodinated testosterone as a tracer. Javanbakht, M. et al., J. Clin. Endocrinol. Metab., 85, No. 7, 2000, pages 2395-401. This assay has a sensitivity of 0.44 ng / dL and a coefficient of variation within and between assays of 13.2 and 8.2%, respectively. Free testosterone levels were measured using a sensitive equilibrium dialysis method (Sinha-Hikim, I et al., J. Clin. Endocrinol. Metab., 83, 1998, optimized to measure low concentrations with high accuracy and accuracy. 1312 to 1318). 200 μL of the serum in the inner fraction was dialyzed against 2.4 mL of dialysis buffer close to the composition of human serum protein-free ultrafiltrate. Ibid. Dialysis was performed at 37 ° C. overnight for 16 hours. Testosterone concentration in the dialysate was measured by RIA using ¹²⁵ I-labeled testosterone. Ibid. The sensitivity of the free testosterone assay is 0.6 pg / ml (2.0 pmol / L) and the coefficient of variation within and between assays is 4.2 and 12.3%, respectively. Serum LH, FSH and SHBG levels were measured with two site-specific immunofluorescence quantitative assays (Delfia-Wallac, Gaithersburg, MD) and the sensitivity was 0.05 U / l, 0.15 U / 0.1, respectively, as described above. 1 and 6.25 nmol / l. Javanbakht et al. And Sinha-Hikim et al., Supra. The intra- and inter-assay coefficients of variation were 10.7% and 13.0% for LH, 3.2% and 11.3% for FSH, and 10% and 10.2% for SHBG, respectively. Serum estradiol levels were measured by radioimmunoassay, sensitivity was 2.5 pg / mL, and intra- and inter-assay coefficients of variation were 8% and 10%, respectively.

Baseline and pharmacokinetic parameters were averaged among subjects within each group to obtain mean values, SD and SEM. Testosterone bioavailability was described as the area under the testosterone curve (AUC). The time-average free and total testosterone concentrations during the 24-hour sampling period were calculated by dividing the area under each curve by 24 hours. The following pharmacokinetic parameters from the 24-hour profile of free and total testosterone measured on days 8, 22 and 35 were evaluated: time average, steady state concentration (C _average ), maximum concentration (C _max ), Lowest concentration (C _min ), highest concentration time (T _max ), lowest concentration time (T _min ) and area under the curve (AUC). C _average was calculated by dividing 24 AUC by 24 hours.

  There were two treatment groups: postmenopausal women who were given testosterone gel alone and were not receiving estrogen therapy, and postmenopausal women who were given a combination of stable hormone replacement therapy including premarin and medroxyprogesterone. Different doses of testosterone gel were administered in random order. Therefore, we analyzed the analysis of variance in a three-way mixed model with the testosterone dose (4.4, 8.8 or 13.2 mg per day), estrogen (yes or no) and time after gel administration as 3 factors ( ANOVA) was used. Patient effects (nesting within treatment) were included in the model as covariance. To simplify the estimation process, we assumed that the tripartite interaction between estrogen treatment, dose, and time was zero, but all two-party interactions including appropriate interaction with nested patient effects. The effect was used in the analysis. Where the F test showed a significant effect, differences between individual groups were analyzed using the Tukey-Kramer multiple comparison method. To satisfy the distributional hypothesis of the ANOVA model, serum hormone concentrations were log transformed before analysis. Analysis of pharmacokinetic parameters across the dose arm used a two-way repeated measures analysis of variance where estrogen treatment was a treatment variable and dose was a repeat factor. The Tukey-Kramer multiple comparison method was used to analyze any significant dose effects.

  The baseline characteristics of the subject were measured. Two groups of women, those who received stable estrogen replacement therapy and those who did not receive estrogen replacement therapy, were in terms of age, weight, height, body mass index, and baseline levels of total and free testosterone in serum There was no significant difference. As shown in Table 21, serum estradiol and SHBG levels were higher and LH and FSH levels were lower in women who were receiving estrogen replacement therapy than women who were not receiving estrogen replacement therapy.

  Testosterone gels were generally well tolerated. In Group I, 1 subject reported acne, 1 subject reported increased hair growth, and 1 subject experienced mild leg swelling. In Group II, 1 subject reported mild erythema at the site of gel administration, 1 subject reported skin oiliness, 2 subjects had acne, 4 subjects had breast tenderness, 3 subjects had vaginal spots. He reported bleeding. There were no significant changes in hemoglobin, AST and ALT during treatment.

  Serum total testosterone levels were low at baseline. As shown in FIGS. 8-11, in both groups of women, serum testosterone concentrations increased in proportion to the dose administered after gel administration. As shown in Table 22, serum total testosterone concentrations on the first day, day 15, and day 29 of each treatment period are not significantly different from baseline levels regardless of testosterone dose, Indicates that the washout period was sufficient to prevent any carryover effect.

  Analysis of variance revealed a significant dose effect of testosterone on serum total testosterone concentration (P = 0.0001). However, there was no significant effect (P = 0.11) of estrogen supplementation on serum testosterone concentrations (FIGS. 8-11). Serum total testosterone levels are significantly different from each other at a co-significant level of 0.05 at all doses, and mean testosterone levels are increased in women who received estrogen as well as women who did not receive estrogen The order of dose levels was. Therefore, mean serum testosterone concentrations were higher during the treatment period with doses of 8.8 and 13.2 mg than at baseline or during the administration period of the 4.4 mg testosterone gel (FIGS. 10 and 11). Administration of the 8.8 and 13.2 mg doses increased serum total testosterone levels from medium to medium high in healthy menstrual women, respectively. Overall, serum total testosterone concentrations did not change significantly during the 24-hour sampling period at any testosterone dose (FIGS. 8 and 9). However, serum total testosterone concentrations began to decline between 24 and 36 hours after gel administration (FIGS. 4 and 5).

  There was no significant effect of estrogen therapy on serum testosterone concentrations at any time during the 24 hour period (P = 0.11). There was no significant interactive effect of testosterone dose and estrogen supplementation status on serum total testosterone levels (P = 0.82). This means that there was no evidence of non-parallelism between the testosterone dose and serum testosterone concentration dose-response curves in women who were and did not receive estrogen.

  The average (Coverage), highest (Cmax) and lowest (Cmin) total testosterone concentrations during the 24-hour gel dosing period are higher than during the 13.2 mg dose, at baseline or during the 4.4 mg dose. Was also significantly higher. However, as shown in Table 23, there was no significant difference in Coverage, Cmax or Cmin between women who had received estrogen replacement and those who had not received estrogen replacement therapy.

As shown in Table 23, T _max and T _min did not differ significantly between the three doses tested. The mean increase in serum total testosterone concentration from baseline (ΔC _average ) was proportional to the dose administered.

  Serum free testosterone levels at baseline were low in both groups of women. Serum free testosterone concentrations are not significantly different from baseline levels at the beginning of each treatment period, regardless of testosterone dose (Table 22), and the 7-day washout period between doses has no carryover effect. It was confirmed that it was enough to stop.

  As shown in FIGS. 12 and 13, the serum free testosterone concentration increased in proportion to the dose administered after administration of the testosterone gel. A very significant testosterone dose effect (P = 0.0003) on free testosterone concentration was observed. However, there was no significant effect of estrogen supplementation (P = 0.96) on serum free testosterone levels. In Tukey-Kramer multiple comparison analysis, serum free testosterone concentrations after administration of 8.8 and 13.2 mg doses were significantly higher than at baseline or during administration of 4.4 mg doses, but at a joint 5% significance level Then it was found that they were not significantly different from each other. There was no effect of estrogen treatment on serum free testosterone concentrations at any time during the 24 hour period and at any dose of testosterone gel. Also, serum free testosterone concentrations were not significantly different at different time points during the 24-hour sampling period at any of the test doses.

As shown in Table 24, the free testosterone concentrations C _average , C _max and C _min during the 24-hour gel administration period increased in proportion to the dose administered, compared to baseline or during administration of the 4.4 mg dose. It was significantly higher in those who received the 13.2 mg dose.

The mean increase in serum free testosterone from baseline was related to testosterone dose. Therefore, ΔC _average was higher during the 13.2 mg dose than during baseline sampling or during the 4.4 mg dose. There was no significant difference in C _average , C _max, and C _min at any dose between women receiving estrogen replacement and women not receiving estrogen replacement therapy.

  As expected, serum estradiol levels were higher in women who were receiving estrogen replacement therapy than those who were not receiving estrogen replacement therapy at baseline (41 ± 3 vs 11 ± 1 pg / mL) and at all time points during testosterone treatment. High (P <0.000001) (FIGS. 14 and 15). Serum estradiol concentration did not change significantly in any group after administration of testosterone gel (P = 0.37). There was no significant interactive effect of testosterone and estrogen treatment on serum estradiol concentration (P = 0.59).

  At baseline, serum FSH levels were significantly lower in women who were receiving estrogen replacement therapy than in women who were not receiving estrogen replacement therapy (43 ± 5 vs 74 ± 7 U / L) (FIGS. 16 and 17). There was a significant difference in FSH levels in subjects who were administered compared to those who did not receive estrogen (P = 0.0001). However, there was no significant effect of testosterone dose in any treatment group (P = 0.33).

  Serum LH concentrations were significantly lower in women who were receiving estrogen replacement therapy than in women who were not receiving estrogen replacement therapy (27 ± 3 vs 35 ± 2 U / L, P = 0.001) (FIGS. 18 and 19). During testosterone administration, serum LH concentrations were significantly different between those who were not receiving estrogen and those who were not (P = 0.0001). However, there was no significant difference in LH levels between different testosterone doses in either group (P = 0.97).

  Serum sex hormone binding globulin (SHBG) levels were numerically higher in women receiving estrogen replacement therapy. However, the difference in SHBG concentration between these two groups did not reach statistical significance (P = 0.21) (P = 0.63) (FIGS. 20 and 21). In either group, serum SHBG levels did not change significantly at any dose during testosterone administration (P = 0.76).

  This example shows that treatment with testosterone gel at low testosterone levels in postmenopausal women was associated with a dose-dependent increase in total and free testosterone concentrations in the serum. Transdermal administration of 8.8 and 13.2 mg testosterone gel daily increased and maintained total and free testosterone levels in the mid to high range in healthy menstrual women. The flatness of the total and free testosterone concentration profile is consistent with relatively uniform testosterone delivery during the 24-hour sampling period following testosterone gel administration. These data justify the once-daily administration of the gel. Hormone replacement therapy with conjugated equine estrogen and medroxyprogesterone acetate did not significantly affect total and free testosterone concentrations throughout the treatment.

Testosterone Dosage in Women After Bilateral Ovariectomy In one embodiment of the invention, the methods, kits, combinations, and compositions comprise testosterone formulations that are transdermally deliverable. In this example, testosterone is formulated as a gel for transdermal administration, as described above in Table 4.

  In a prophetic example, 24 premenopausal women who underwent bilateral oophorectomy were randomized to (a) deliver 1.7 mg / day of testosterone to the skin, about 0.1 mg of which was absorbed 0.17 g / day of RELIBRA for 30 days, or (b) 0.25 g / day of RELIBRA that delivers 2.5 mg / day of testosterone to the skin to absorb about 0.15 mg for 30 days Or (c) Deliver 5 mg / day of testosterone to the skin and administer 0.5 g / day of RELIBRA that absorbs about 0.3 mg for 30 days, or (d) administer a gel containing placebo for 30 days. The gel is rubbed once a day onto clean, dry skin on the upper outside of the thigh and waist. After application, the gel is air dried. Patient wash hands

  Applicant expects from a physiological point of view that all test parameters show an improvement over placebo in female sexual dysfunction. Therefore, Applicants expect that in premenopausal women who have undergone bilateral oophorectomy, RELIBRA can be administered to improve female sexual dysfunction compared to placebo.

Testosterone and methyltestosterone dosages in women after bilateral oophorectomy In one embodiment of the present invention, methods, kits, combinations and compositions comprise testosterone formulations capable of transdermal delivery and methyltestosterone formulations capable of oral delivery. Consists of. In this example, testosterone is formulated as a gel for transdermal administration as described above in Table 4, methyltestosterone is formulated as a capsule for oral administration, and each dosage unit contains 10 mg of methyltestosterone. .

  In a prophetic example, 24 premenopausal women who underwent bilateral oophorectomy were randomized in addition to 30 days of daily oral doses of 10 mg or 50 mg methyltestosterone, (a) 1. 7 mg / day of testosterone is delivered to the skin and about 0.1 mg is absorbed, 0.17 g / day of RELIBRA for 30 days, or (b) 2.5 mg / day of testosterone is delivered to the skin and about 0.25 g / day of RELIBRA that absorbs 0.15 mg for 30 days, or (c) 0.5 g / day of RELIBRA that delivers about 5 mg / day of testosterone to the skin and absorbs about 0.3 mg Administer gel containing 30 days or (d) placebo for 30 days. The gel is rubbed once a day onto clean, dry skin on the upper outside of the thigh and waist. After application, the gel is air dried. The patient cleans his hands.

  Applicant expects from a physiological point of view that all test parameters show an improvement over placebo in female sexual dysfunction. Therefore, applicants expect that RELIBRA can be administered in combination with methyltestosterone to improve female sexual dysfunction compared with placebo in premenopausal women who have undergone bilateral oophorectomy .

Testosterone and Estrogen Dosages in Women After Bilateral Ovariectomy In one embodiment of the present invention, methods, kits, combinations and compositions are derived from testosterone formulations capable of transdermal delivery and estrogen formulations capable of parenteral delivery. Become. In this example, testosterone is formulated as a gel for transdermal administration as described above in Table 4, and estradiol is formulated as a gel for transdermal administration as described above in Table 6.

  In a prophetic example, 24 premenopausal women who underwent bilateral oophorectomy were randomized in addition to 30 days of 5 days or 10 grams of ESTROGEL, (a) 1.7 mg / Deliver about 0.1 mg of testosterone daily to the skin and absorb about 0.1 mg of 0.17 g / day of RELIBRA for 30 days, or (b) Deliver 2.5 mg / day of testosterone to the skin for about. 0.25 g / day of RELIBRA that absorbs 15 mg for 30 days, or (c) 0.5 g / day of RELIBRA that delivers 5 mg / day of testosterone to the skin and absorbs about 0.3 mg for 30 days Or (d) administering a gel containing a placebo for 30 days. The gel is rubbed once a day onto clean, dry skin on the upper outside of the thigh and waist. After application, the gel is air dried. The patient cleans his hands.

  Applicant expects from a physiological point of view that all test parameters show an improvement over placebo in female sexual dysfunction. Therefore, Applicants expect that RELIBRA can be co-administered with estradiol to improve female sexual dysfunction compared to placebo in premenopausal women who have undergone bilateral oophorectomy.

  The gel is rubbed once a day onto clean, dry skin on the upper outside of the thigh and waist. After application, the gel is air dried. The patient cleans his hands. Application of the gel results in elevated testosterone levels with a desirable pharmacokinetic profile similar to that of normal women. Gels are therefore useful for treating several conditions or diseases in women.

In Vitro Skin Permeation Test Method The skin permeation of the testosterone and other therapeutic agents of the present invention can be measured using the following method. Diffusion cells are used with hairless mouse skin or human cadaver skin.

  The composition is applied to the skin and rubbed into a predetermined area for uniform contact with the skin. The resulting composition / skin is placed with the composition side up and across the lower opening of the diffusion cell. Assemble the diffusion cell and fill the bottom with 10 mL of warm (32 ° C.) receiving fluid so that the receiving fluid is in contact with the skin. The receiving fluid is stirred using a magnetic stirrer. Cover the sampling port unless it is in use.

  The cell is then placed in a constant temperature (32 ° C.) and constant humidity (50% relative humidity) bath. To ensure sample uniformity and reduced diffusion barrier on the dermal side of the skin, the receiving fluid is agitated by a magnetic stirrer throughout the experiment. Withdraw the entire amount of receiving fluid at specified time intervals and immediately refill with new fluid. The withdrawn fluid is filtered through a 0.45 μM filter and then analyzed for testosterone or therapeutic agent using high performance liquid chromatography. Calculate the cumulative amount of testosterone or therapeutic agent that has penetrated the skin and the flow rate.

  The contents of all references cited throughout this application are expressly incorporated herein by reference. The practice of the present invention uses conventional pharmacological and pharmacological techniques unless otherwise stated, and these are within the skill of the art.

  Although the invention has been described with reference to specific embodiments and examples, it should be understood that other embodiments utilizing the concepts of the invention are possible without departing from the scope of the invention. . The invention is defined by the claimed elements, and any and all modifications, variations, or equivalents that fall within the true spirit and scope of the underlying principles.

1 is a graph showing baseline total testosterone (ng / dL) before administration of 4.4 mg or 8.8 mg testosterone in 1% hydroalcoholic testosterone gel for pre-menopausal and post-menopausal women. FIG. 6 is a graph showing total testosterone (ng / dL) on day 7 from treatment with administration of 4.4 mg or 8.8 mg testosterone in 1% hydroalcoholic testosterone gel for pre-menopausal and post-menopausal women. 1 is a graph showing total testosterone (ng / dL) with 4.4 mg or 8.8 mg administration of 1% hydroalcoholic testosterone gel in premenopausal women. FIG. 2 is a graph showing free testosterone (ng / dL) by administration of 4.4 mg or 8.8 mg of 1% hydroalcoholic testosterone gel in premenopausal women. 1 is a graph showing total testosterone (ng / dL) with 4.4 mg or 8.8 mg administration of 1% hydroalcoholic testosterone gel in postmenopausal women. FIG. 2 is a graph showing free testosterone (ng / dL) by administration of 4.4 mg or 8.8 mg of 1% hydroalcoholic testosterone gel in postmenopausal women. FIG. 6 is a graph showing the increase in serum testosterone (ng / dL) by administration of 4.4 mg or 8.8 mg testosterone in 1% aqueous alcohol testosterone gel for pre-menopausal and post-menopausal women. 2 is a graph showing total testosterone concentration during baseline sampling or during administration of different doses of testosterone gel or placebo in postmenopausal women who have not received supplemental estrogen therapy. 2 is a graph showing total testosterone concentrations during baseline sampling or during administration of different doses of testosterone gel or placebo in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing the average testosterone concentration during baseline sampling or during administration of different doses of testosterone gel or placebo in postmenopausal women who have not received supplemental estrogen therapy. 2 is a graph showing the average testosterone concentration during baseline sampling or administration of different doses of testosterone gel or placebo in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing serum free testosterone concentrations during baseline sampling or during administration of different doses of testosterone gel or placebo in postmenopausal women who have not received supplemental estrogen therapy. 2 is a graph showing serum free testosterone concentrations during baseline sampling or during administration of different doses of testosterone gel or placebo in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing estradiol concentration during baseline sampling or administration of different doses of testosterone gel in postmenopausal women who were not receiving supplemental estrogen therapy. 2 is a graph showing estradiol concentration during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing FSH concentrations during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women who were not receiving supplemental estrogen therapy. 2 is a graph showing FSH concentrations during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing LH concentration during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women who were not receiving supplemental estrogen therapy. 2 is a graph showing LH concentrations during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women receiving supplemental estrogen therapy. 2 is a graph showing SHBG concentrations during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women who were not receiving supplemental estrogen therapy. 2 is a graph showing SHBG concentrations during baseline sampling or during administration of different doses of testosterone gel in postmenopausal women receiving supplemental estrogen therapy.

Claims (29)

A method for treating, preventing or reducing the risk of developing testosterone deficiency disorder in a female subject in need thereof, comprising:
(I) identifying a female subject having or at risk for developing testosterone deficiency disorder;
(Ii) administering an amount of a hydroalcoholic gel pharmaceutical composition to a region of the subject's skin, the amount delivering a therapeutically effective amount of testosterone to the subject's serum, resulting in a testosterone deficiency disorder Or the risk of developing testosterone deficiency disorder is reduced, the composition of which
a. About 0.1% to about 10% (w / w) testosterone, or a salt, ester, amide, enantiomer, isomer, tautomer, prodrug or derivative thereof;
b. About 30% to about 98% (w / w) alcohol selected from the group consisting of ethanol or isopropanol;
c. About 0.1% to about 5% (w / w) penetration enhancer;
d. From about 0.1% to about 5% (w / w) gelling agent; and e. Including balanced pure water,
The composition is capable of releasing testosterone to the skin at a rate and for a period that increases the testosterone serum concentration to at least about 3 pg testosterone / ml serum within about 24 hours after administration.   The method of claim 1, wherein the composition comprises about 1% testosterone.   The method of claim 1, wherein the composition comprises about 67% alcohol.   The method of claim 1, wherein the penetration enhancer is isopropyl myristate.   The method of claim 1, wherein the composition comprises about 0.5% isopropyl myristate.   The method of claim 1, wherein the gelling agent is selected from the group consisting of polyacrylic acid and carboxymethylcellulose.   The method of claim 1, wherein the gelling agent is polyacrylic acid present in an amount of about 1% by weight of the composition. The composition is
a. About 1.0% testosterone,
b. About 0.9% CARBOPOL (registered trademark),
c. About 0.5% isopropyl myristate,
d. About 67% ethanol, and e. Including balanced pure water,
The method of claim 1, wherein these percentages are weight ratios to the composition.   The method of claim 1, wherein for about 0.1 gram of application of the composition to the skin per day, an increase in serum testosterone concentration of at least about 5 ng / dl occurs in the subject.   The method of claim 1, wherein the composition is provided to the subject for daily administration at a dose of about 0.1 g to about 10 g.   The method of claim 1, wherein the amount of the composition is a 0.44 g dose and delivers about 0.44 mg to about 44 mg of testosterone to the skin.   The method of claim 1, wherein the amount of the composition is a 1.32 g dose and delivers about 1.32 mg to about 132 mg of testosterone to the skin.   The method of claim 1, wherein the amount of the composition is a 1.32 g dose and delivers 6.6 mg to about 13.2 mg of testosterone to the skin.   12. The method of claim 11, wherein the amount of the composition is a 0.44 g dose and delivers about 4.4 mg of testosterone to the skin or a 0.88 g dose and delivers about 8.8 mg of testosterone to the skin.   15. The method of claim 14, wherein the subject is premenopausal with a subnormal free (unbound) testosterone concentration of less than 0.5 ng / dl.   15. The method of claim 14, wherein the subject has a subnormal free (unbound) testosterone concentration of less than 0.5 ng / dl and is postmenopausal.   The method of claim 1, wherein the composition is delivered to the subject in one or more packets.   The method of claim 17, wherein the packet comprises a polyethylene liner between the composition and the inner surface of the packet.   The method of claim 1, wherein the composition is administered once, twice or three times a day.   2. The method of claim 1, wherein the composition further comprises about 0.01% to about 69% of a therapeutic agent comprising an agent that inhibits the synthesis of sex hormone binding globulin, progesterone, progestin, or estrogenic hormone.   21. The method of claim 20, wherein the therapeutic agent comprises about 1% to about 10% of the composition.   21. The method of claim 20, wherein the therapeutic agent is progesterone.   24. The method of claim 22, wherein the serum level of progesterone increases to at least about 1 ng progesterone / ml serum within about 24 hours of administration.   21. The method of claim 20, wherein the therapeutic agent is estrogen.   25. The method of claim 24, wherein the serum level of estrogen increases to at least 60 pg estrogen / ml serum within about 24 hours of administration.   21. The method of claim 20, wherein the therapeutic agent is methyltestosterone.   21. The method of claim 20, wherein the therapeutic agent is estradiol. A method for improving sexual performance in a female subject in need thereof comprising: (a) administering an amount of a hydroalcoholic gel pharmaceutical composition to an area of the subject's skin, the method comprising: The amount is one that delivers a therapeutically effective amount of testosterone to the serum of the subject, the composition comprising: i. About 0.1% to about 10% (w / w) testosterone, or a salt, ester, amide, enantiomer, isomer, tautomer, prodrug or derivative thereof;
ii. About 30% to about 98% (w / w) alcohol selected from the group consisting of ethanol or isopropanol;
iii. About 0.1% to about 5% (w / w) penetration enhancer;
iv. From about 0.1% to about 5% (w / w) gelling agent; and v. A step including balance water;
(B) administering an amount of an agent that improves sexual performance.   29. The method of claim 28, wherein the agent is selected from the group consisting of agents that cause vasodilation, nitrates, alpha blockers, natural prostaglandins, endothelium-derived relaxing factors, phosphodiesterase inhibitors, or combinations thereof. .

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